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The Journal of Neuroscience, March 15, 1999, 19(6):1895-1911

Differential Distribution of Three Members of a Gene Family Encoding Low Voltage-Activated (T-Type) Calcium Channels

Edmund M. Talley¹, Leanne L. Cribbs², Jung-Ha Lee², Asif Daud², Edward Perez-Reyes², and Douglas A. Bayliss¹

¹ Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, and ² Department of Physiology, Loyola University Medical Center, Maywood, Illinois 60153

	ABSTRACT

Top Abstract Introduction References

Low voltage-activated (T-type) calcium currents are observed in many central and peripheral neurons and display distinct physiological and functional properties. Using in situ hybridization, we have localized central and peripheral nervous system expression of three transcripts (1G, 1H, and 1I) of the T-type calcium channel family (Ca_VT). Each mRNA demonstrated a unique distribution, and expression of the three genes was largely complementary. We found high levels of expression of these transcripts in regions associated with prominent T-type currents, including inferior olivary and thalamic relay neurons (which expressed 1G), sensory ganglia, pituitary, and dentate gyrus granule neurons (1H), and thalamic reticular neurons (1I and 1H). Other regions of high expression included the Purkinje cell layer of the cerebellum, the bed nucleus of the stria terminalis, the claustrum (1G), the olfactory tubercles (1H and 1I), and the subthalamic nucleus (1I and 1G). Some neurons expressed high levels of all three genes, including hippocampal pyramidal neurons and olfactory granule cells. Many brain regions showed a predominance of labeling for 1G, including the amygdala, cerebral cortex, rostral hypothalamus, brainstem, and spinal cord. Exceptions included the basal ganglia, which showed more prominent labeling for 1H and 1I, and the olfactory bulb, the hippocampus, and the caudal hypothalamus, which showed more even levels of all three transcripts. Our results are consistent with the hypothesis that differential gene expression underlies pharmacological and physiological heterogeneity observed in neuronal T-type calcium currents, and they provide a molecular basis for the study of T-type channels in particular neurons.

Key words: in situ hybridization; calcium channel; CNS; anticonvulsant; rat; T-type calcium channels

	INTRODUCTION

Top Abstract Introduction References

Voltage-dependent calcium channels play a dual role in the CNS; they couple electrical activity to calcium influx, thereby triggering myriad intracellular biochemical events, and they contribute to membrane properties that determine the precise nature of excitability in different cell types. Low voltage-activated (LVA) calcium channels have a hand in both of these roles that is readily distinguishable from their high voltage-activated (HVA) counterparts, in part because they activate at potentials near the resting membrane potential. First, in addition to participating in spike-induced calcium entry (McCobb and Beam, 1991; Scroggs and Fox, 1992b; Umemiya and Berger, 1994), they allow calcium influx at potentials below threshold. This influx can occur when cells are at rest (Magee et al., 1996) or in response to subthreshold synaptic inputs (Miyakawa et al., 1992; Markram and Sakmann, 1994; Magee et al., 1995). Second, LVA calcium channels can be a crucial component in shaping subthreshold membrane fluctuations and thereby contribute to such behaviors as rebound burst firing (Llinas and Yarom, 1981), rhythmic oscillation (Gutnick and Yarom, 1989; Bal and McCormick, 1993), and resonance (Hutcheon et al., 1994; Puil et al., 1994). Given their proposed role in oscillatory behavior, it is perhaps not surprising that LVA calcium channel dysfunction is implicated in epileptiform activity (Tsakiridou et al., 1995) and that these channels are targets for antiepileptic drugs (Coulter et al., 1989b).

Information regarding the structure of calcium channels has been determined primarily from the cloning of genes that encode the subunits forming HVA calcium channels. The central core of these channels consists of an 1 subunit that has four internal repeats, each repeat consisting of six membrane-spanning regions and a pore-forming loop (for review, see Catterall, 1995; Perez-Reyes and Schneider, 1995). Currently, at least six 1 subunits have been identified that are believed to generate the physiologically and pharmacologically defined HVA calcium channel subtypes (generally designated L, N, P, Q, and R). Although one of these subunits (1E) expresses currents that are transient and whose voltage-dependent properties suggest that it may encode an LVA channel (Soong et al., 1993), the currents produced by this gene do not possess all of the properties that are common for "T-type" LVA calcium channels (e.g., Randall and Tsien, 1997). T-type properties in neurons include low voltage activation, strongly voltage-dependent kinetics, rapid inactivation, slow deactivation, and small single-channel conductance (for review, see Huguenard, 1996).

Recently, a subfamily of genes (designated Ca_VT) has been discovered encoding 1 subunits that are ~30% homologous to HVA subunit genes in their putative membrane-spanning regions (Cribbs et al., 1998; Perez-Reyes et al., 1998a,b). When expressed heterologously, two of these proteins, 1G and 1H, show all the properties hallmark of neuronal T-type calcium channels. A third member of this family, designated 1I, also encodes a calcium channel that displays a number of T-type properties (Lee et el., 1999).

Given that expression of T-type channels has a unique impact on neuronal properties, it is of great interest to know which neuronal populations express these subunits. Furthermore, T-type channels are pharmacologically and physiologically heterogeneous (Akaike et al., 1991; Huguenard, 1996; Tarasenko et al., 1997). This heterogeneity may reflect different functions of these channels in neurons, and may stem at least in part from differential expression of each of these three genes. Therefore, using in situ hybridization histochemistry, we have localized the regional and cellular distribution of gene expression for the three known members of the Ca_VT family in the rat central and peripheral nervous systems. We find that each gene has a unique expression pattern and that the location of these three channel types is to a large extent complementary.

	MATERIALS AND METHODS

Tissue preparation. Male Sprague Dawley rats (250-350 gm; Hilltop) were anesthetized with ketamine-xylazine and decapitated. Brains, spinal cords, and ganglia were removed and frozen on dry ice. Sections (10 µm) were thaw-mounted onto charged slides (Superfrost Plus; Fisher Scientific, Houston, TX) and stored at 80°C for later use. In preliminary experiments, sagittal and horizontal sections were used from six animals. For detailed comparative analysis, coronal sections from three animals were taken from the entire brain (~200-500 µm apart). In addition, representative sections from three or four animals were taken from nodose, superior cervical, and dorsal root ganglia, as well as from cervical, thoracic, and lumbar spinal cord. Slides were pretreated for hybridization as described previously (Talley et al., 1997). Sections were fixed in 4% paraformaldehyde (5 min) and rinsed extensively with PBS, pH 7.4. They were treated with glycine (0.2% in PBS; 5 min) and acetic anhydride (0.25% in 0.1 M triethanolamine, 0.9% saline, pH 8; 10 min) and subsequently dehydrated in a graded series of ethanols and chloroform. Hybridization was performed overnight at 37°C in a buffer of 50% formamide, 4× SSC (1× SSC: 150 mM NaCl and 15 mM sodium citrate, pH 7), 1× Denhardt's solution (0.02% each of Ficoll, polyvinylpyrrolidone, and bovine serum albumin), 10% dextran sulfate, 100 mM DTT, 250 µg/ml yeast tRNA, and 0.5 mg/ml salmon testes DNA. After hybridization, slides were washed through four changes of 1× SSC at 55°C (15 min each) and once for an hour in 1× SSC at room temperature.

Oligonucleotide probes. Sequence analysis of 1G, 1H, and 1I has revealed a high degree of homology in the putative transmembrane regions of these three genes (Perez-Reyes et al., 1998b). In contrast, there is particularly low conservation in the sequences that connect each of the four repeating domains. Therefore, antisense oligonucleotide probes (33 bases in length) were designed to hybridize to the cytoplasmic I-II "linker" region of the rat homolog of each gene (L. L. Cribbs, J.-H. Lee, and E. Perez-Reyes, unpublished data). Sequences were chosen that had minimal homology both to other calcium channel genes and to other sequences present in GenBank. Probes were labeled using terminal deoxyribonucleotidyl transferase (Life Technologies, Gaithersburg, MD); unincorporated nucleotides were removed using Sephadex G-50 spin columns (Pharmacia, Piscataway, NJ).

Multiple oligonucleotides were used to probe each gene (three oligonucleotides for 1G, three for 1H, and two for 1I). Subsequent to preliminary experiments characterizing the probes, the oligonucleotides corresponding to each gene were hybridized in a cocktail. We found that using the probes in combination resulted in an enhanced signal but had no effect on relative distribution of signal intensities in different brain regions (see below). The concentration of each oligonucleotide was ~30 × 10⁶ cpm/ml (~2 nM). The sequences of the probes were as follows: 1G: 5'-CCAGCCCGCACGCCTATAGCCCTAGAGACCTGG-3', 5'-TCCGATGGGCATCTGGGAGGGGGTGCCTGGCAA-3', and 5'-TGTCGCCGCCGGCTGTGGGGATCCCGGAGGTCA-3'; 1H: 5'-ATGCCGTACATCCTGGGTAAACTCATAGACTCC-3', 5'-AGCCCCTTGGGTCGTGAGCTGGTGCCACCTTTG-3', and 5'-ATCCCTCCTGGTTGTGAGGCCTTCCGCAGTGGT-3'; 1I: 5'-AGCCACCAGAACCTGAGCCTTCCTGGCCTGAGT-3' and 5'-TCGCGCCACACATCCCCACACAGTCGGGCTGCC-3'.

Control experiments. We performed a number of preliminary control experiments. First, we hybridized each oligonucleotide separately to sagittal and horizontal sections. Cognate oligonucleotides generated an identical tissue distribution, indicating that these independent probes recognized the same gene product and ruling out the possibility of spurious cross-reactivity. Higher wash temperatures (60 and 65°C in 1× SSC) resulted in diminished hybridization, but for each oligonucleotide the distribution of labeling was unchanged, indicating that the same binding site was labeled in different brain areas. For each set of probes, specific binding was eliminated by prior digestion with RNase A (50 µg/ml; Boehringer Mannheim, Indianapolis, IN). Nonspecific binding was assessed in competition experiments (examples of which are shown in Fig. 3), with ~500-fold excess unlabeled oligonucleotide (1 µM) included in the hybridization mixture. In these experiments, nonspecific binding to tissue was barely distinguishable from the overall background, demonstrating that specific binding was saturable and that nonspecific binding was minimal.

Data analysis and presentation. Slides were exposed to film (Hyperfilm -MAX; Amersham, Arlington Heights, IL) for 1 week to generate autoradiograms (Fig. 1), which were analyzed with the aid of image analysis software (MCID; Imaging Research) to determine the relative intensity of labeling in different brain regions. For resolution of cellular labeling, slides also were dipped in liquid autoradiographic emulsion (NTB2; Eastman Kodak, Rochester, NY), exposed for 5-9 weeks, and examined by dark-field and bright-field microscopy. Images of silver grains from these slides (see Figs. 2-7) were captured using a Pixera video camera mounted on a Leitz Diaplan microscope. In addition, high-power bright-field micrographs (such as those shown in Figs. 4, 6, 7) were made of labeled cells from different brain regions for side-by-side comparison of the relative numbers of silver grains overlaying various cell types.

View larger version (171K): [in this window] [in a new window]   View larger version (160K): [in this window] [in a new window]   View larger version (164K): [in this window] [in a new window]   View larger version (141K): [in this window] [in a new window]   Figure 1.   CNS distribution of CaVT gene expression. Sections were hybridized with oligonucleotides specific for 1G (left panels), 1H (middle panels), and 1I (right panels) and exposed to autoradiographic film. Line drawings on the far right are adapted from Paxinos and Watson (1997; reproduced with permission) and indicate the relevant labeled areas. For abbreviations, refer to Table 2.

By combining densitometry of film autoradiograms with information on the specific cellular localization of hybridization, we determined the comparative distribution of each of the three transcripts. The results of this analysis are presented in Table 1 as a system of pluses, with five pluses (+++++) representing the highest levels of expression. It is important to understand that because a number of factors other than transcript levels (particularly the hybridization efficiency of individual probes) can affect signal intensity, this scoring system reflects relative amounts of individual transcripts in different brain regions, rather than comparisons among the three different Ca_VT transcripts. However, the fact that the various probes to each gene (when hybridized individually) generated similar signal intensities suggests that the influence of factors such as differences in hybridization efficiency were minor. Therefore, relative levels of the three different mRNA species may be compared, so long as such comparison is viewed with caution. In this regard, it is also important to note that only two probes were used to detect 1I (as opposed to three each for 1G and 1H). As stated above, we found that combining oligonucleotides in a cocktail had no effect on relative distribution but resulted in enhanced signal intensity. Thus, because one fewer probe was used for 1I, transcript levels for this gene may have been somewhat under-represented relative to those of the other two genes.

View this table: [in this window] [in a new window]   Table 1.   Distribution of 1G/1H/1I mRNA

	RESULTS

Overview

We performed in situ hybridization to determine the regional distribution of Ca_VT (1G, 1H, and 1I) gene expression in the central and peripheral nervous systems. Figure 1 shows representative film autoradiograms of transverse sections that were taken through the entire brain. Figures 2-7 show representative dark-field and bright-field images of silver grains from emulsion-dipped slides. The results of combined analysis from film autoradiograms and emulsion-dipped slides are summarized in Table 1.

View larger version (95K): [in this window] [in a new window]   Figure 2.   Dark-field micrographs demonstrating cellular labeling of olfactory structures. Slides were exposed to autoradiographic emulsion; silver grains were imaged using dark-field microscopy. Left panels show silver grains over cells of the main olfactory bulb. Note that whereas all three transcripts were present in the granule cell layer (asterisks), labeling of small neurons in the glomerular layer (arrowheads) was limited to 1G and 1I. Right panels show the olfactory tubercles. Labeling for 1H and 1I was very high in the cell islands of Calleja (open arrows); labeling was also high for 1H but only moderate for 1I in the dense cell layer of the tubercles (closed arrows). Scale bar, 500 µm.

View larger version (124K): [in this window] [in a new window]   Figure 3.   Dark-field micrographs of horizontal sections through the ventral portion of the hippocampus. Left panels show cross sections in the horizontal plane through the ventral hippocampus. Note that whereas all three transcripts were present, each had a different relative distribution through the various hippocampal fields. Fields CA1 and CA3 are indicated, as are the dentate gyrus (DG), the subiculum (S), and the ventral lateral geniculate nucleus (VLG) of the thalamus. Open arrow points to 1G-labeled (presumably nonpyramidal) cells in stratum radiatum. The dentate gyrus is shown at higher magnification in the middle panels. Note that the granule cell layer (Gr, arrowheads in all three sets of panels) shows particularly strong labeling for 1H, whereas cells of the polymorph layer (Po) show more even levels of the three transcripts. Right panels show images of the dentate gyrus from control sections hybridized in the presence of ~500-fold excess cold oligonucleotide. Note that this nonspecific labeling was uniformly low. Scale bar, 400 µm (left panels); 100 µm (middle and right panels).

View larger version (135K): [in this window] [in a new window]   Figure 4.   Differential hybridization to neurons in the cerebral cortex. Distribution of 1G, 1H, and 1I mRNA in the primary somatosensory cortex is shown at increasing levels of magnification. Top panels demonstrate laminar distribution of labeling; the relevant cortical layers (layers II-VI) are indicated to the right of these panels, as are the external capsule (ec) and the striatum (CPu). Arrowheads indicate large (presumably pyramidal) neurons in layer V. The same neurons are depicted at higher magnification in the middle panels (using dark-field optics) and at still higher magnification in bottom panels (using bright-field optics). Note that 1G and 1I were found in all cortical layers, but expression of 1H was for the most part restricted to layer V. Scale bar, 400 µm (top panels); 100 µm (middle panels); 25 µm (bottom panels).

View larger version (112K): [in this window] [in a new window]   Figure 5.   Distribution of CaVT expression in the thalamus. Left panels show differential labeling of the thalamic reticular nucleus (Rt) and ventral posterior thalamic nucleus (VP). Note that neurons of the reticular nucleus contained 1H and 1I mRNA, whereas 1G expression was limited to thalamic relay nuclei, including VP. Right panels show labeling in the habenulae and midline thalamic nuclei. Neurons of the lateral habenular nucleus (LHb) expressed 1G and 1I mRNA (see Results for details). DG, Dentate gyrus; PV, paraventricular thalamic nucleus. Scale bar, 250 µm.

View larger version (160K): [in this window] [in a new window]   Figure 6.   Parasagittal sections demonstrating labeling of the cerebellum and inferior olivary nucleus. Left panels show bright-field images of film autoradiograms exposed to sagittal sections through the brainstem and cerebellum. Lobules 9 and 1 of the cerebellar vermis are indicated and correspond to higher magnification dark-field micrographs of emulsion-dipped sections shown on the right. Note that for 1G, the granule cell layer (Gr) of the cerebellum displayed a rostrocaudal gradient of expression, with lobule 9 labeled intensely and lobule 1 showing very low levels. In contrast, expression of 1I in the granule cell layer was fairly uniform throughout the cerebellum and showed similar levels in both lobules. Probes for 1G labeled Purkinje neurons (P) at extremely high levels. One of these neurons (arrowhead) is depicted at higher power using bright-field optics (inset). The inferior olivary nucleus (InO) also is indicated in the autoradiograms and corresponds to dark-field images in the bottom panels. Labeling of this structure also was heterogeneous: 1G was uniformly high; labeling for 1I was limited to the caudal part of the nucleus. Scale bar, ~4.8 mm (left panels); 250 µm (right panels); 50 µm (inset); 400 µm (bottom panels).

View larger version (137K): [in this window] [in a new window]   Figure 7.   Differential accumulation of CaVT transcripts in the spinal cord and sensory ganglia. Left panels show low-power dark-field images of transverse sections through the lumbar spinal cord. All three transcripts were present in the dorsal horn (asterisks), with 1H mRNA limited to neurons of the external lamina. Note also that 1G and 1H were expressed in motor neurons in the ventral horn (open arrows). Middle panels show high-power bright-field images of dorsal root ganglia (DRG) neurons. Probes for 1H and 1I labeled small- and medium-sized neurons (arrowheads); in contrast, large neurons (asterisks) were unlabeled. In the nodose ganglia (right panels) expression was for the most part limited to 1H (arrowhead). Scale bar, 400 µm (left panels); 25 µm (middle and right panels).

The distribution of the three transcripts was to a great extent complementary, and the expression pattern of each gene was unique. Only a few regions, including the granule cell layer of the olfactory bulb (Figs. 1A, 2), fields CA1 and CA3 of the hippocampus (Figs. 1G-K, 3), and the tenia tecta (TT; Fig. 1B), displayed expression of all three transcripts in abundance. Cells with the highest 1G mRNA levels included cerebellar Purkinje cells (Fig. 6), thalamic relay neurons (Fig. 5), inferior olivary cells (InO; Fig. 6), and neurons of the bed nucleus of the stria terminalis (BST; Fig. 1E). Labeling for 1H was highest in the olfactory tubercle (Tu; Figs. 1C,D, 2), granule cells of the dentate gyrus (Figs. 1G-K, 3), and in sensory ganglia (Fig. 7). Labeling for 1I was highest in the olfactory bulb (Figs. 1A, 2), the cell islands of Calleja (ICj; Figs. 1C, 2), and fields CA1 and CA3 of the hippocampus (Figs. 1G-K, 3).

Olfactory system

All three probes gave prominent labeling in the olfactory bulb (MOB; Figs. 1A, 2). As noted above, the granule cell layer of this structure was one of a limited number of brain regions with high expression of all three channel subtypes. In contrast, the mitral cell layer was not noticeably labeled, and where mitral cells were identified by Nissl stain, silver grains were not detected above background (data not shown). Small neurons in the glomerular layer contained moderate levels of 1G, whereas 1I was present at very high levels in scattered members of this cell population (Fig. 2).

Moderate to high levels of message were also found for all three genes in olfactory cortical structures, including the anterior olfactory nucleus (AO; Fig. 1A) and piriform cortex (Pir; Fig. 1B-I; see below). The olfactory tubercle, by contrast, had an expression pattern that was more reminiscent of the striatum (see below) insofar as it contained little expression of 1G mRNA (Figs. 1B-D, 2). Instead, it contained very high levels of 1H in the dense cellular layer as well as very high levels of 1H and 1I in the cellular islands of Calleja.

Basal forebrain

1H and 1I transcripts were both present throughout the striatum (CPu; Figs. 1C-I, 4) and the accumbens nucleus (Acb; Fig. 1B,C). 1H was detected at moderate levels in these structures, whereas 1I distribution was mixed: it was found at barely detectable levels in the accumbens and the medial striatum, but it displayed moderate levels at the lateral and caudal edges of the striatum. 1G mRNA was generally undetectable in these structures, although scattered cells were labeled: these were more evident medially at the edge of the globus pallidus (GP), a nucleus that was not marked by expression of any of the transcripts (Fig. 1E-H). Another basal ganglia structure, the subthalamic nucleus (STh; Fig. 1I) contained high levels of 1I, moderate levels of 1G, and only scattered expression of 1H.

In the septum (Fig. 1C-E), labeling was moderate for 1G in the dorsal and ventral part of the lateral septum (LSD, LSV) and low in the intermediate part (LSI) and in the medial septum (MS). 1H labeling was found at low levels in all parts of the lateral and medial septum and absent in the triangular septum (TS). Labeling for 1I was opposite to that of 1H; it was not detected in the lateral and medial septum, but it was present in low amounts in the triangular septum. This region is traversed by a cortical structure, the indusium griseum (IG; Fig. 1C), which had very high levels of 1H as well as low levels of 1G.

The BST (Fig. 1D,E) displayed expression for all three genes, but only in the medial edge of the posterior region of the nucleus. In this restricted area, 1G expression was quite high, 1H was moderate, and 1I was low. In the rest of the nucleus, levels of 1G and 1H expression were low, and 1I expression was not detected. Another basal forebrain structure, the claustrum (Cl; Fig. 1B-F), also had prominent 1G expression along with low levels of 1I.

View this table: [in this window] [in a new window]   Table 2.   Abbreviations used throughout text and in figures

Amygdala

In the amygdala, 1G and 1H were predominant, with 1I mRNA expressed at low levels in most nuclei (Fig. 1G-K). Highest levels of all three genes were found in the nucleus of the lateral olfactory tract (LOT; Fig. 1F) and the related bed nucleus of the accessory olfactory tract (BAOT; Fig. 1G). In the central nucleus (Ce; Fig. 1G,H) and the lateral nucleus (La; Fig. 1G-I), 1H expression was uniformly low, but 1G expression was varied; it was higher in medial portions of the central nucleus and in lateral portions of the lateral nucleus. In the medial amygdala, by contrast, expression for all three genes was mixed; it was higher in the posterior part (MeP; Fig. 1H,I) than in the anterior part (MeA; Fig. 1G). Expression for 1G and 1H was most evident in the caudal tip of this nucleus, as shown in Figure 1I.

Hippocampal formation

In many CNS regions, the hybridization levels of the 1G probes tended to be higher than those of the other two sets of probes. Such was not the case for the hippocampal formation (Fig. 1G-L, 3), where labeling intensities were more equivalent between the three sets of probes. Pyramidal cells in the hippocampus had moderate to high levels of all three transcripts, whereas Ca_VT expression in the nonpyramidal cell layers of Ammon's Horn was, for the most part, restricted to 1G. In the granule cell layer of the dentate gyrus, 1H expression was predominant and extremely high. In contrast, dentate gyrus polymorph cells had labeling that was more closely matched between the three sets of probes.

Cerebral cortex

All three transcripts were present in the cerebral cortex, as shown in Figures 1A-L and 4, 1G and 1I were present fairly uniformly in all cell layers, the major exception being layer IV, where both transcripts were detectable in more cells. In addition, in the ventral part of the cortex just dorsal to the claustrum, a band of neurons that was intensely labeled with the probes for 1G was present in the deepest part of layer VI. These intensely labeled cells appeared to be restricted to the insular/perirhinal cortices (Ins, Fig. 1B-G; PRh, Fig. 1H-K) and secondary somatosensory areas (e.g., Fig. 1E). With respect to particular cell types, probes for 1G and 1I labeled both large (presumably pyramidal) and small (presumably granule) neurons. However, this labeling was not uniform, and in some cells expression was not detected. Thus, no clear preference emerged for expression of either one of these transcripts by specific types of cortical neurons.

Such a general distribution in the neocortex was not the case for 1H. It was seen at very high levels in a subset of layer V pyramidal neurons; otherwise it was only present at very low levels in the externalmost cellular layer (layer II) and was not detected in layers IV and VI. The 1H-expressing pyramidal neurons were predominantly found in the deeper part of layer V, although not every large neuron at this level was labeled.

Two rostral cortical structures expressed all three transcripts at high levels. One was the TT (Fig. 1B). The other structure, the Pir (Fig. 1B-I), had mixed expression levels of all three genes. Both 1H and 1I were present in high amounts in the superficial neurons of this cortical region but were not detected in deeper layers. On the other hand, 1G mRNA was expressed in moderate amounts in the external layer but at much higher levels in the deeper layers, especially the dorsal endopiriform nucleus (DEn; Fig. 1C-J).

Thalamus

The thalamus (Figs. 1E-K, 5) was characterized by high levels of expression of 1G in thalamocortical relay nuclei. In many of these nuclei, including the medial dorsal (MD), the ventral anterior (VA), the ventral and posterior relay nuclei (Po, VM, and VP), and the medial and dorsal lateral geniculate nuclei (MG and DLG), detectable expression was limited to 1G. Low levels of 1I were seen in the anterior dorsal nucleus (AD; Fig. 1F) and the rostral part of the lateral dorsal nucleus (LD; Fig. 1G); low to moderate levels were seen in the ventral lateral geniculate nucleus (VLG; Fig. 1J). Expression of 1H in relay nuclei was limited to some of the large neurons of AD that expressed this transcript at low levels. The intralaminar nuclei, including the central medial nucleus (CM; Fig. 1G,H), paraventricular thalamic nucleus (PV; Fig. 1F-I), the rhomboid (Rh; Fig. 1G), and reuniens (Re; Fig. 1G,H) nuclei had even higher levels of 1G expression. Low levels of 1I expression also characterized a number of these nuclei (CM, PV, and Rh).

In contrast to the thalamic relay and intralaminar nuclei, the thalamic reticular nucleus, which is composed of GABAergic interneurons that modulate and synchronize thalamic output (for review, see Steriade et al., 1993), had no detectable 1G expression (Fig. 5, left panels). Instead, these neurons expressed high levels of 1I and moderate levels of 1H. The lateral habenula (Fig. 5, right panels) had an uneven distribution of 1G and 1I; both transcripts were detected at high levels in the rostral portion of the nucleus. Caudally, 1I expression was moderate, and 1G expression was low (Fig. 1, compare H, I). Ca_VT expression was not detected in neurons of the medial habenula, a region characterized by high levels of mRNA encoding 1E (Soong et al., 1993; Williams et al., 1994).

Hypothalamus

In the hypothalamus, 1G was predominant rostrally. In the preoptic region (Fig. 1D-F), 1G mRNA levels were higher in medial structures such as the medial preoptic nucleus (MPO) than in their lateral counterparts (e.g., LPO). This medial bias also included the rostral portion of the suprachiasmatic nucleus (SCh; Fig. 1E,F). More caudally, expression levels were mixed. Expression of all three genes was found in both the dorsomedial (DM) and the ventromedial (VMH) nuclei, with high levels of 1G mRNA in the ventrolateral portion of the VMH (Fig. 1H,I). Expression patterns in the mammillary bodies were somewhat complex, with each transcript showing a unique expression pattern (Fig. 1J). In the medial mammillary nucleus, the medial part (MM) showed a predominance of 1H expression, whereas the lateral part (ML) displayed 1G and 1I. In the lateral mammillary nucleus (LM), 1G was abundant, with the other two transcripts present only at low levels.

Midbrain and pons

All three transcripts were expressed in the tectum (SupC and IC; Fig. 1K-M), with 1H and 1I at low levels and 1G at low to moderate levels, except in the external gray area of the superior colliculus, where 1G labeling was high (Fig. 1K). All three transcripts also were found in the pretectal nuclei (MPT and APT; Fig. 1J), which were notable as a result of high 1H labeling in scattered cells of the anterior pretectal nucleus (APT). The periaqueductal gray (PAG; Fig. 1J-L) had moderate levels of labeling for 1G and low levels of 1H. More caudally, the tegmental nuclei ventral to the fourth ventricle (Fig. 1M,N) were a little more heterogeneous, with 1G mRNA at high levels in the posterodorsal tegmental nucleus (PDTg; Fig. 1N) and 1I present in the laterodorsal nucleus (LDTg; Fig. 1M).

Labeling for 1G and 1H were found at low levels in the raphe nuclei (Fig. 1K,L). These two transcripts were also found in the substantia nigra (SN; Fig. 1J,K); in the compact part 1G labeling was moderate and 1H low, whereas the reticular part was for the most part unlabeled, except for some cells that contained 1H (data not shown). All three transcripts were found in the interpeduncular nucleus (IP; Fig. 1K) with 1G and 1H at moderate levels and 1I at low levels. The lateral parabrachial nucleus (LPB; Fig. 1M,N) had low levels of 1G and 1H, except for the external portion, which had moderate to high levels of 1G (Fig. 1M). One other area of note was the pontine nuclei (not shown), which had low to moderate levels of both 1G and 1I.

Cerebellum and inferior olive

Expression of Ca_VT transcripts in the cerebellum is illustrated in Figures 1M-P and 6. 1G expression was strikingly high in every Purkinje cell examined, and granule cells were labeled with 1G probes in a rostral-to-caudal gradient of increasing levels of expression (in both the hemispheres and the vermis), as has been seen for a variety of cerebellar markers (Herrup and Kuemerle, 1997). 1I mRNA also was present in the granule cell layer at moderate levels, although it lacked the graded expression seen for 1G. The InO (Figs. 1O,P, 6) also contained 1G and 1I mRNA; in this case 1G was expressed at very high levels throughout the nucleus, whereas 1I was expressed at moderate levels, but only in caudal olivary neurons.

Medulla and spinal cord

In the medulla and in the spinal cord, probes for 1G mRNA once again generated a higher signal than did those for 1H and 1I. Labeling for all three transcripts was sparse or absent in brainstem reticular areas, including those of the midbrain and pons (Fig. 1L-N). In the medullary reticular fields, 1G was present at low levels in the lateral but not the medial areas (Fig. 1O, compare PCRt, Gi); 1I was found in the lateral reticular nucleus (Fig. 1P).

All three transcripts were detected in sensory areas. In the spinal trigeminal nucleus (Sp5), the three mRNAs were found at higher levels caudally than rostrally (Fig. 1, compare O, P). All three also were seen in the dorsal cochlear nucleus (data not shown), but only 1G was present (and at lower levels) in the ventral cochlear nucleus (VC; Fig. 1M,N). Similarly, all three transcripts were present in the dorsal horn of the spinal cord (Fig. 7). 1G was present at moderate levels; 1H was for the most part restricted to the outermost layers (layers 1-2). 1I was somewhat more evenly distributed at low levels, but it was more prominent in layers 3-4. Only 1G and 1H were detected in the nucleus of the solitary tract (Sol; Fig. 1O,P).

Somatic motor neurons in the brainstem and spinal cord contained 1G and 1H mRNA, at moderate and low levels, respectively (Figs. 1M,P, 7). Other labeled medullary regions included the inferior olive (discussed above) and the area postrema (AP; Fig. 1P); in the AP all three transcripts were found, with 1G at high levels.

Other areas

In addition to surveying the CNS, we also hybridized the Ca_VT probes to sections from the sensory and sympathetic ganglia, specifically the nodose, dorsal root ganglia (DRG) and superior cervical ganglia. High-power bright-field micrographs of sensory neurons of the DRG and nodose ganglia are shown in Figure 7 (middle and left panels). In the DRG, high levels of 1H and moderate levels of 1I mRNA were found in scattered medium-sized neurons, whereas the extremely large neurons were not labeled. The nodose ganglia also contained high levels of 1H mRNA in many neurons, although in contrast to the DRG, there did not appear to be a bias in the size of the labeled neurons. Neurons of the superior cervical ganglia (not shown) only expressed very low levels of 1G. We also examined cells of the pituitary and pineal glands. Both of these structures showed high levels of expression of 1H mRNA (data not shown).

	DISCUSSION

We used in situ hybridization to show that three members of a novel family of calcium channels with T-type properties are expressed widely in the CNS and in peripheral neurons, and that each of these three transcripts has a unique pattern of distribution. Our results reveal that expression of these genes is prominent in a number of brain areas where T-type currents have been recorded and absent in specific regions believed to be devoid of these currents. Furthermore, our data are in accord with the hypothesis that differential expression of specific Ca_VT subtypes may account for at least some of the heterogeneity observed in CNS T-type calcium currents.

Ca_VT transcripts are expressed in cells with prominent T-type currents

As anticipated, we detected robust expression of Ca_VT mRNA in areas where prominent T-type calcium currents have been observed. For example, we found expression of all three transcripts in the thalamus, where the role of T-type calcium channels has been studied extensively (for review, see Steriade et al., 1993). We found 1G mRNA to be predominant in thalamocortical relay areas but absent in the thalamic reticular nucleus, which instead expressed high and moderate levels of 1I and 1H mRNA, respectively. It is believed that the differences in the characteristics of T-type currents in these two cell types (discussed below) are important for the generation of synchronized thalamocortical rhythms (McCormick and Bal, 1997).

Another region classically associated with prominent T-type calcium current is the InO, where we found 1G mRNA in great abundance. LVA currents in these neurons contribute to oscillations that support the coordination of synchronous rhythmic firing (Manor et al., 1997). These neurons make monosynaptic contacts with Purkinje cells of the cerebellum, and their synchronous activity is believed to play a prominent role in the organization of cerebellar output (Welsh et al., 1995). It is worth pointing out that we found a heterogeneous distribution of Ca_VT transcripts in the InO. Expression in the rostral part of the nucleus was restricted to 1G, whereas caudal expression consisted of both 1G and 1I (Figs. 1O,P, 6). It remains to be determined how this differential distribution of Ca_VT expression in the inferior olive might contribute to the functional organization of olivocerebellar processing.

In addition to 1G and 1I, we also found abundant 1H mRNA in regions commonly associated with prominent T-type calcium currents. For example, we found high levels of this transcript in granule cells of the dentate gyrus and in sensory ganglion neurons. In both of these cell types, T-type channels have been shown to produce sizable spike afterdepolarizing potentials (White et al., 1989; Zhang et al., 1993) that in sensory neurons can trigger bursts of action potentials. It is notable that in sensory neurons of the nodose ganglia, Ca_VT gene expression has been directly implicated in the production of T-type calcium current; transfection with an antisense oligonucleotide targeting a sequence shared by the three Ca_VT genes specifically and markedly diminished the LVA calcium current in those cells (Lambert et al., 1998).

In sensory neurons of DRG, we saw high expression of 1H and moderate levels of 1I mRNA. Expression of both transcripts was restricted to small- and medium-sized neurons; Ca_VT transcripts were not found in the extremely large DRG neurons. These data are in accord with studies of calcium currents of DRG neurons acutely isolated from adult rats, where large T-type currents were present in medium-diameter neurons but were absent in large-diameter neurons (Scroggs and Fox, 1992a). Thus, our results support the view that T-type currents are expressed specifically in smaller sensory neurons that convey thermal and nociceptive information and not in larger neurons that subserve proprioceptive and tactile pathways (Scroggs and Fox, 1992a).

In addition to finding abundant Ca_VT mRNA in areas where prominent T-type calcium currents have been observed, there were a number of regions where we saw little or no detectable Ca_VT expression and where other investigators have failed to find LVA calcium current. For example, we saw no Ca_VT expression in the globus pallidus and saw only very low expression of one of the transcripts (1G) in sympathetic ganglia. In neurons of both of these areas, T-type channels were not evident in whole-cell calcium current recordings (Schofield and Ikeda, 1988; Plummer et al., 1989; Surmeier et al., 1994).

Regions of inconsistency between Ca_VT expression and recordings of T-type calcium currents

As noted above, we saw expression of Ca_VT transcripts in regions that display prominent T-type currents and failed to detect these transcripts in regions where T-type currents are absent. However, there were also a number of regions reportedly devoid of these currents where Ca_VT genes were expressed (e.g., granule cells in the cerebellum and cerebral cortex) and conversely, regions where T-type currents have been recorded but where we found no evidence for Ca_VT expression (e.g., olfactory mitral cells).

It is important to point out that comparative characterization of T-type currents in neurons is problematic because a variety of experimental factors can affect these recordings (discussed in Huguenard, 1996). A particular concern for comparing T-type currents is the converging evidence suggesting that a substantial fraction of these channels are localized to relatively distal dendrites (Karst et al., 1993; Markram and Sakmann, 1994; Magee and Johnston, 1995; Kavalali et al., 1997; Mouginot et al., 1997). As a result of this subcellular distribution, recordings from intact neurons are subject to voltage- and space-clamp errors that can have a dramatic impact on the apparent voltage- and time-dependent properties of T-type calcium currents generated at distal sites (Destexhe et al., 1996, 1998). However, in dissociated preparations where electrical recordings only sample currents from the soma and proximal dendrites, the complement of calcium channels of a cell may be misrepresented. Therefore, in addition to some of the more obvious caveats to comparison (e.g., species or age differences in the animals being compared), it is important to note that definitive identification and characterization of T-type currents in neurons is difficult and may even be subject to "false negatives."

One region where there were discrepancies between Ca_VT expression and T-type current recordings was the cerebellum. For example, Purkinje cells are most often associated with their prominent P-type HVA calcium currents (Mintz et al., 1992), and it has been suggested that T-type currents in these neurons, which are robust in neonatal animals (Regan, 1991), might only be transiently expressed early during postnatal development (Usowicz et al., 1992, but see Kaneda et al., 1990). However the data presented here, which show extremely high levels of 1G mRNA in adult Purkinje cells (Fig. 6), do not support this possibility. Moreover, our preliminary results indicate that expression of 1G mRNA is present in the neonate and actually increases postnatally (E. M. Talley and D. A. Bayliss, unpublished observations).

Similar to Purkinje neurons, cerebellar granule cells also have been studied extensively for the characterization of their HVA current (Slesinger and Lansman, 1991; Pearson et al., 1995; Randall and Tsien, 1995), and T-type currents are reported to be absent in these neurons (Rossi et al., 1994). However, we found a prominent distribution of Ca_VT expression in these cells. It is noteworthy that this distribution was heterogeneous. Although moderate levels of 1I were found evenly distributed in granule cells throughout the cerebellar cortex, 1G was found at high levels only in the caudal lobules of both the vermis and the hemispheres (Fig. 6A,B). This type of gradient also has been observed for expression of K_V4.2 and K_V4.3 (Serodio and Rudy, 1998), two genes believed to contribute to transient subthreshold potassium currents. Thus, based on the expression of Ca_VT- and K_V4-family genes, we would expect to find differences in subthreshold membrane properties of rostral and caudal cerebellar granule neurons.

Another area of the CNS where there is curious inconsistency between our findings with regard to Ca_VT expression and experiments examining the characteristics of neuronal calcium currents is the cerebral cortex. T-type calcium currents are thought to be more prominent in pyramidal neurons of the neocortex (Giffin et al., 1991; Hamill et al., 1991) when compared with nonpyramidal cells. Furthermore, cells with measurable T-type current were predominantly found in deeper layers, cortical layer V in the visual cortex (Giffin et al., 1991) or layers V and VI in the medial frontal cortex (de la Pena and Geijo-Barrientos, 1996). In accord with those studies, we found that 1H expression is largely limited to layer V pyramidal neurons. However, we also found substantial expression of 1G and 1I in all cortical layers, and this expression did not appear to be limited to pyramidal neurons. Given the generalized expression patterns of 1G and 1I in the neocortex, it is not clear why only a restricted population of neurons in this region have been found to display T-type currents.

In addition to observing Ca_VT expression in neurons thought to be devoid of T-type currents, there were also cells in which we failed to find Ca_VT expression but which appear to have T-type calcium currents. This was the case for olfactory mitral cells, which have been shown to have LVA currents of modest amplitude (Wang et al., 1996). However, although they appear to lack expression of known Ca_VT gene-family members, these cells are well stained by an antibody to the 1E (HVA family) calcium channel (Yokoyama et al., 1995). It is possible that LVA currents in these neurons receive a contribution from the 1E channel, which can generate currents with some T-type properties (Soong et al., 1993; Meir and Dolphin, 1998) and may account for some of the LVA current in atrial myocytes (Piedras-Renteria et al., 1997). An alternative possibility is that an as yet unidentified gene accounts for the LVA currents in mitral cells. It is worth mentioning at this juncture that in contrast to mitral cells, we found high levels of expression of all three transcripts in granule cells of the olfactory bulb. Calcium currents in these neurons apparently have not been extensively characterized (Bhalla and Bower, 1993).

Heterogeneity of CNS T-type calcium currents

CNS T-type calcium channels are pharmacologically and physiologically heterogeneous, leading to the hypothesis that at least some of their variability is generated by differences in genes encoding these channels. With respect to pharmacology, T-type currents have shown different sensitivities to block by a number of cations and organic compounds (for review, see Akaike, 1991; Huguenard, 1996). Any discussion of the contribution of the three Ca_VT gene products to this differential sensitivity is preliminary because the pharmacological profiles of these clones have not been extensively characterized. It can be pointed out, however, that we do not see any correlation between the expression profiles of any of the three Ca_VT transcripts and regions where particular pharmacological attributes have been observed. For example, differential sensitivities to both nickel and amiloride have been noted between DRG neurons and pituitary cells (Todorovic and Lingle, 1998), two regions where we see predominant expression of 1H mRNA. Conversely, thalamic reticular and relay neurons, which express different Ca_VT transcripts, have similar sensitivities to both nickel and amiloride (Huguenard and Prince, 1992).

Physiological characterization of the three Ca_VT genes has been performed, and there appears to be some correlation between expression of these genes and the properties of T-type currents in different CNS neurons. When expressed in the same cell type (HEK 293 cells), 1G and 1H generate currents with similar kinetic and voltage-dependent properties. In contrast, 1I currents have slower kinetics and depolarized voltage dependence of activation, when compared with the other two channels (Lee et el., 1999).

The contrast in properties between the 1I channels and those of 1G and 1H corresponds to a difference in T-type currents in different cells of the thalamus, a region where these currents have been extensively characterized both in dissociated and intact preparations (Destexhe et al., 1996, 1998). When calcium currents were compared directly in thalamic reticular and thalamic relay neurons (Coulter et al., 1989a; Huguenard and Prince, 1992), it was found that the LVA component was distinctly different in the two cell types. Thalamic reticular neurons, which express high levels of 1I mRNA along with moderate levels of 1H, had slower kinetics of activation and inactivation when compared with thalamic relay neurons of the ventral basal complex, a region that appears to exclusively express 1G. Moreover, in reticular neurons the voltage range of activation was depolarized relative to that of relay neurons. Given data from the expressed channels, it appears that the slower kinetics and depolarized voltage dependence of activation in reticular neurons may result at least in part from their expression of 1I. Consistent with this hypothesis, neurons of the lateral habenula, which express both 1G and 1I (Figs. 4H,I, 5), were found to have T-current with physiological properties intermediate between those of reticular and relay neurons (Huguenard et al., 1993).

It should be pointed out that in addition to Ca_VT (1I and 1H) expression, thalamic reticular neurons also apparently express somewhat elevated levels of 1E (Soong et al., 1993; Williams et al., 1994; but see Yokoyama et al., 1995). As noted above, this gene is more rapidly inactivating and has a more hyperpolarized threshold for activation than other genes of the HVA family (Soong et al., 1993). Therefore, it may be that a combination of 1E, 1H, and 1I contribute to the LVA current in thalamic reticular neurons. In addition, we cannot rule out the possibility that there may be as yet uncloned genes that generate and/or modify LVA currents in these and other CNS neurons.

	FOOTNOTES

Received Sept. 23, 1998; revised Oct. 28, 1998; accepted Oct. 30, 1998.

This work was supported by National Institutes of Health Grants HL57828 (E.P-R.), NS33583 (D.A.B.), and MH12091 (predoctoral fellowship for E.M.T.). We thank Drs. Madaline B. Harrison, Ruth L. Stornetta, Patrice G. Guyenet, and the Information Technology Services at the University of Virginia for providing imaging equipment and support.

Correspondence should be addressed to Edmund M. Talley, Department of Pharmacology, Box 448, Health Sciences Center, University of Virginia, Charlottesville, VA 22908.

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				C. Hu, S. D. DePuy, J. Yao, W. E. McIntire, and P. Q. Barrett Protein Kinase A Activity Controls the Regulation of T-type CaV3.2 Channels by G{beta}{gamma} Dimers J. Biol. Chem., March 20, 2009; 284(12): 7465 - 7473. [Abstract] [Full Text] [PDF]

				P. Orestes, D. Bojadzic, R. M. Chow, and S. M. Todorovic Mechanisms and Functional Significance of Inhibition of Neuronal T-Type Calcium Channels by Isoflurane Mol. Pharmacol., March 1, 2009; 75(3): 542 - 554. [Abstract] [Full Text] [PDF]

				W. L. Ernst, Y. Zhang, J. W. Yoo, S. J. Ernst, and J. L. Noebels Genetic Enhancement of Thalamocortical Network Activity by Elevating {alpha}1G-Mediated Low-Voltage-Activated Calcium Current Induces Pure Absence Epilepsy J. Neurosci., February 11, 2009; 29(6): 1615 - 1625. [Abstract] [Full Text] [PDF]

				G. Wang and S. M. Thompson Maladaptive Homeostatic Plasticity in a Rodent Model of Central Pain Syndrome: Thalamic Hyperexcitability after Spinothalamic Tract Lesions J. Neurosci., November 12, 2008; 28(46): 11959 - 11969. [Abstract] [Full Text] [PDF]

				M. D. Johnson and C. C. McIntyre Quantifying the Neural Elements Activated and Inhibited by Globus Pallidus Deep Brain Stimulation J Neurophysiol, November 1, 2008; 100(5): 2549 - 2563. [Abstract] [Full Text] [PDF]

				D. Z. Wetmore, E. A. Mukamel, and M. J. Schnitzer Lock-and-Key Mechanisms of Cerebellar Memory Recall Based on Rebound Currents J Neurophysiol, October 1, 2008; 100(4): 2328 - 2347. [Abstract] [Full Text] [PDF]

				L. Nie, J. Zhu, M. A. Gratton, A. Liao, K. J. Mu, W. Nonner, G. P. Richardson, and E. N. Yamoah Molecular Identity and Functional Properties of a Novel T-Type Ca2+ Channel Cloned From the Sensory Epithelia of the Mouse Inner Ear J Neurophysiol, October 1, 2008; 100(4): 2287 - 2299. [Abstract] [Full Text] [PDF]

				H. Vacher, D. P. Mohapatra, and J. S. Trimmer Localization and Targeting of Voltage-Dependent Ion Channels in Mammalian Central Neurons Physiol Rev, October 1, 2008; 88(4): 1407 - 1447. [Abstract] [Full Text] [PDF]

				M. M. Jagodic, S. Pathirathna, P. M. Joksovic, W. Lee, M. T. Nelson, A. K. Naik, P. Su, V. Jevtovic-Todorovic, and S. M. Todorovic Upregulation of the T-Type Calcium Current in Small Rat Sensory Neurons After Chronic Constrictive Injury of the Sciatic Nerve J Neurophysiol, June 1, 2008; 99(6): 3151 - 3156. [Abstract] [Full Text] [PDF]

				J. Tao, M. E. Hildebrand, P. Liao, M. C. Liang, G. Tan, S. Li, T. P. Snutch, and T. W. Soong Activation of Corticotropin-Releasing Factor Receptor 1 Selectively Inhibits CaV3.2 T-Type Calcium Channels Mol. Pharmacol., June 1, 2008; 73(6): 1596 - 1609. [Abstract] [Full Text] [PDF]

				S. Liu and M. T. Shipley Multiple Conductances Cooperatively Regulate Spontaneous Bursting in Mouse Olfactory Bulb External Tufted Cells J. Neurosci., February 13, 2008; 28(7): 1625 - 1639. [Abstract] [Full Text] [PDF]

				J.-M. Israel, D. A. Poulain, and S. H. R. Oliet Oxytocin-Induced Postinhibitory Rebound Firing Facilitates Bursting Activity in Oxytocin Neurons J. Neurosci., January 9, 2008; 28(2): 385 - 394. [Abstract] [Full Text] [PDF]

				T. Inoue and B. W. Strowbridge Transient Activity Induces a Long-Lasting Increase in the Excitability of Olfactory Bulb Interneurons J Neurophysiol, January 1, 2008; 99(1): 187 - 199. [Abstract] [Full Text] [PDF]

				M. T. Nelson, P. M. Joksovic, P. Su, H.-W. Kang, A. Van Deusen, J. P. Baumgart, L. S. David, T. P. Snutch, P. Q. Barrett, J.-H. Lee, et al. Molecular Mechanisms of Subtype-Specific Inhibition of Neuronal T-Type Calcium Channels by Ascorbate J. Neurosci., November 14, 2007; 27(46): 12577 - 12583. [Abstract] [Full Text] [PDF]

				M. R. Kasten, B. Rudy, and M. P. Anderson Differential regulation of action potential firing in adult murine thalamocortical neurons by Kv3.2, Kv1, and SK potassium and N-type calcium channels J. Physiol., October 15, 2007; 584(2): 565 - 582. [Abstract] [Full Text] [PDF]

				M. Cataldi, V. Lariccia, V. Marzaioli, A. Cavaccini, G. Curia, D. Viggiano, L.M.T. Canzoniero, G. di Renzo, M. Avoli, and L. Annunziato Zn2+ Slows Down CaV3.3 Gating Kinetics: Implications for Thalamocortical Activity J Neurophysiol, October 1, 2007; 98(4): 2274 - 2284. [Abstract] [Full Text] [PDF]

				O. Ibanez-Sandoval, L. Carrillo-Reid, E. Galarraga, D. Tapia, E. Mendoza, J. C. Gomora, J. Aceves, and J. Bargas Bursting in Substantia Nigra Pars Reticulata Neurons In Vitro: Possible Relevance for Parkinson Disease J Neurophysiol, October 1, 2007; 98(4): 2311 - 2323. [Abstract] [Full Text] [PDF]

				S. E. Hammack, I. Mania, and D. G. Rainnie Differential Expression of Intrinsic Membrane Currents in Defined Cell Types of the Anterolateral Bed Nucleus of the Stria Terminalis J Neurophysiol, August 1, 2007; 98(2): 638 - 656. [Abstract] [Full Text] [PDF]

				M. T. Nelson, J. Woo, H.-W. Kang, I. Vitko, P. Q. Barrett, E. Perez-Reyes, J.-H. Lee, H.-S. Shin, and S. M. Todorovic Reducing Agents Sensitize C-Type Nociceptors by Relieving High-Affinity Zinc Inhibition of T-Type Calcium Channels J. Neurosci., August 1, 2007; 27(31): 8250 - 8260. [Abstract] [Full Text] [PDF]

				M. E. Hildebrand, L. S. David, J. Hamid, K. Mulatz, E. Garcia, G. W. Zamponi, and T. P. Snutch Selective Inhibition of Cav3.3 T-type Calcium Channels by G{alpha}q/11-coupled Muscarinic Acetylcholine Receptors J. Biol. Chem., July 20, 2007; 282(29): 21043 - 21055. [Abstract] [Full Text] [PDF]

				M. A. Diana, Y. Otsu, G. Maton, T. Collin, M. Chat, and S. Dieudonne T-Type and L-Type Ca2+ Conductances Define and Encode the Bimodal Firing Pattern of Vestibulocerebellar Unipolar Brush Cells J. Neurosci., April 4, 2007; 27(14): 3823 - 3838. [Abstract] [Full Text] [PDF]

				P. M. Joksovic, A. Doctor, B. Gaston, and S. M. Todorovic Functional Regulation of T-Type Calcium Channels by S-Nitrosothiols in the Rat Thalamus J Neurophysiol, April 1, 2007; 97(4): 2712 - 2721. [Abstract] [Full Text] [PDF]

				M. M. Jagodic, S. Pathirathna, M. T. Nelson, S. Mancuso, P. M. Joksovic, E. R. Rosenberg, D. A. Bayliss, V. Jevtovic-Todorovic, and S. M. Todorovic Cell-Specific Alterations of T-Type Calcium Current in Painful Diabetic Neuropathy Enhance Excitability of Sensory Neurons J. Neurosci., March 21, 2007; 27(12): 3305 - 3316. [Abstract] [Full Text] [PDF]

				I. Vitko, I. Bidaud, J. M. Arias, A. Mezghrani, P. Lory, and E. Perez-Reyes The I-II Loop Controls Plasma Membrane Expression and Gating of Cav3.2 T-Type Ca2+ Channels: A Paradigm for Childhood Absence Epilepsy Mutations J. Neurosci., January 10, 2007; 27(2): 322 - 330. [Abstract] [Full Text] [PDF]

				B. Coste, M. Crest, and P. Delmas Pharmacological Dissection and Distribution of NaN/Nav1.9, T-type Ca2+ Currents, and Mechanically Activated Cation Currents in Different Populations of DRG Neurons J. Gen. Physiol., January 1, 2007; 129(1): 57 - 77. [Abstract] [Full Text] [PDF]

				A. Traboulsie, J. Chemin, M. Chevalier, J.-F. Quignard, J. Nargeot, and P. Lory Subunit-specific modulation of T-type calcium channels by zinc J. Physiol., January 1, 2007; 578(1): 159 - 171. [Abstract] [Full Text] [PDF]

				J. Qiu, M. A. Bosch, K. Jamali, C. Xue, M. J. Kelly, and O. K. Ronnekleiv Estrogen Upregulates T-Type Calcium Channels in the Hypothalamus and Pituitary J. Neurosci., October 25, 2006; 26(43): 11072 - 11082. [Abstract] [Full Text] [PDF]

				I. Splawski, D. S. Yoo, S. C. Stotz, A. Cherry, D. E. Clapham, and M. T. Keating CACNA1H Mutations in Autism Spectrum Disorders J. Biol. Chem., August 4, 2006; 281(31): 22085 - 22091. [Abstract] [Full Text] [PDF]

				P. M. Joksovic, M. T. Nelson, V. Jevtovic-Todorovic, M. K. Patel, E. Perez-Reyes, K. P. Campbell, C.-C. Chen, and S. M. Todorovic CaV3.2 is the major molecular substrate for redox regulation of T-type Ca2+ channels in the rat and mouse thalamus J. Physiol., July 15, 2006; 574(2): 415 - 430. [Abstract] [Full Text] [PDF]

				A. I. Ivanov and R. L. Calabrese Graded Inhibitory Synaptic Transmission Between Leech Interneurons: Assessing the Roles of Two Kinetically Distinct Low-Threshold Ca Currents J Neurophysiol, July 1, 2006; 96(1): 218 - 234. [Abstract] [Full Text] [PDF]

				H. Khosravani and G. W. Zamponi Voltage-gated calcium channels and idiopathic generalized epilepsies. Physiol Rev, July 1, 2006; 86(3): 941 - 966. [Abstract] [Full Text] [PDF]

				C. Tai, J. B. Kuzmiski, and B. A. MacVicar Muscarinic enhancement of R-type calcium currents in hippocampal CA1 pyramidal neurons. J. Neurosci., June 7, 2006; 26(23): 6249 - 6258. [Abstract] [Full Text] [PDF]

				R. R. Llinas and M. Steriade Bursting of Thalamic Neurons and States of Vigilance J Neurophysiol, June 1, 2006; 95(6): 3297 - 3308. [Abstract] [Full Text] [PDF]

				X. Zhong, J. R. Liu, J. W. Kyle, D. A. Hanck, and W. S. Agnew A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies Hum. Mol. Genet., May 1, 2006; 15(9): 1497 - 1512. [Abstract] [Full Text] [PDF]

				V. S. Sohal, S. Pangratz-Fuehrer, U. Rudolph, and J. R. Huguenard Intrinsic and synaptic dynamics interact to generate emergent patterns of rhythmic bursting in thalamocortical neurons. J. Neurosci., April 19, 2006; 26(16): 4247 - 4255. [Abstract] [Full Text] [PDF]

				M. L. Molineux, J. E. McRory, B. E. McKay, J. Hamid, W. H. Mehaffey, R. Rehak, T. P. Snutch, G. W. Zamponi, and R. W. Turner Specific T-type calcium channel isoforms are associated with distinct burst phenotypes in deep cerebellar nuclear neurons PNAS, April 4, 2006; 103(14): 5555 - 5560. [Abstract] [Full Text] [PDF]

				M. Uebachs, C. Schaub, E. Perez-Reyes, and H. Beck T-type Ca2+ channels encode prior neuronal activity as modulated recovery rates J. Physiol., March 15, 2006; 571(3): 519 - 536. [Abstract] [Full Text] [PDF]

				K. L. Blethyn, S. W. Hughes, T. I. Toth, D. W. Cope, and V. Crunelli Neuronal Basis of the Slow (<1 Hz) Oscillation in Neurons of the Nucleus Reticularis Thalami In Vitro J. Neurosci., March 1, 2006; 26(9): 2474 - 2486. [Abstract] [Full Text] [PDF]

				M. L. Molineux, F. R. Fernandez, W. H. Mehaffey, and R. W. Turner A-Type and T-Type Currents Interact to Produce a Novel Spike Latency-Voltage Relationship in Cerebellar Stellate Cells J. Neurosci., November 23, 2005; 25(47): 10863 - 10873. [Abstract] [Full Text] [PDF]

				M. Cordero-Erausquin, J. A. M. Coull, D. Boudreau, M. Rolland, and Y. D. Koninck Differential Maturation of GABA Action and Anion Reversal Potential in Spinal Lamina I Neurons: Impact of Chloride Extrusion Capacity J. Neurosci., October 19, 2005; 25(42): 9613 - 9623. [Abstract] [Full Text] [PDF]

				B. E McKay and R. W Turner Physiological and morphological development of the rat cerebellar Purkinje cell J. Physiol., September 15, 2005; 567(3): 829 - 850. [Abstract] [Full Text] [PDF]

				L. Autret, I. Mechaly, F. Scamps, J. Valmier, P. Lory, and G. Desmadryl The involvement of Cav3.2/{alpha}1H T-type calcium channels in excitability of mouse embryonic primary vestibular neurones J. Physiol., August 15, 2005; 567(1): 67 - 78. [Abstract] [Full Text] [PDF]

				I. Nikonenko, M. Bancila, A. Bloc, D. Muller, and P. Bijlenga Inhibition of T-Type Calcium Channels Protects Neurons from Delayed Ischemia-Induced Damage Mol. Pharmacol., July 1, 2005; 68(1): 84 - 89. [Abstract] [Full Text] [PDF]

				P. M Joksovic, D. A Bayliss, and S. M Todorovic Different kinetic properties of two T-type Ca2+ currents of rat reticular thalamic neurones and their modulation by enflurane J. Physiol., July 1, 2005; 566(1): 125 - 142. [Abstract] [Full Text] [PDF]

				I. Vitko, Y. Chen, J. M. Arias, Y. Shen, X.-R. Wu, and E. Perez-Reyes Functional Characterization and Neuronal Modeling of the Effects of Childhood Absence Epilepsy Variants of CACNA1H, a T-Type Calcium Channel J. Neurosci., May 11, 2005; 25(19): 4844 - 4855. [Abstract] [Full Text] [PDF]

				D. M. Rodman, K. Reese, J. Harral, B. Fouty, S. Wu, J. West, M. Hoedt-Miller, Y. Tada, K.-X. Li, C. Cool, et al. Low-Voltage-Activated (T-Type) Calcium Channels Control Proliferation of Human Pulmonary Artery Myocytes Circ. Res., April 29, 2005; 96(8): 864 - 872. [Abstract] [Full Text] [PDF]

				A. Pignatelli, K. Kobayashi, H. Okano, and O. Belluzzi Functional properties of dopaminergic neurones in the mouse olfactory bulb J. Physiol., April 15, 2005; 564(2): 501 - 514. [Abstract] [Full Text] [PDF]

				M. P. Anderson, T. Mochizuki, J. Xie, W. Fischler, J. P. Manger, E. M. Talley, T. E. Scammell, and S. Tonegawa Thalamic Cav3.1 T-type Ca2+ channel plays a crucial role in stabilizing sleep PNAS, February 1, 2005; 102(5): 1743 - 1748. [Abstract] [Full Text] [PDF]

				L. I. Brueggemann, B. L. Martin, J. Barakat, K. L. Byron, and L. L. Cribbs Low voltage-activated calcium channels in vascular smooth muscle: T-type channels and AVP-stimulated calcium spiking Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H923 - H935. [Abstract] [Full Text] [PDF]

				S.-N. Yang and P.-O. Berggren {beta}-Cell CaV channel regulation in physiology and pathophysiology Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E16 - E28. [Abstract] [Full Text] [PDF]

				V. Crunelli, T. I. Toth, D. W. Cope, K. Blethyn, and S. W. Hughes The 'window' T-type calcium current in brain dynamics of different behavioural states J. Physiol., January 1, 2005; 562(1): 121 - 129. [Abstract] [Full Text] [PDF]

				P. Isope and T. H. Murphy Low threshold calcium currents in rat cerebellar Purkinje cell dendritic spines are mediated by T-type calcium channels J. Physiol., January 1, 2005; 562(1): 257 - 269. [Abstract] [Full Text] [PDF]

				J. Lee, D. Kim, and H.-S. Shin Lack of delta waves and sleep disturbances during non-rapid eye movement sleep in mice lacking {alpha}1G-subunit of T-type calcium channels PNAS, December 28, 2004; 101(52): 18195 - 18199. [Abstract] [Full Text] [PDF]

				J. Murbartian, J. M. Arias, and E. Perez-Reyes Functional Impact of Alternative Splicing of Human T-Type Cav3.3 Calcium Channels J Neurophysiol, December 1, 2004; 92(6): 3399 - 3407. [Abstract] [Full Text] [PDF]

				Z.-Z. Wu, S.-R. Chen, and H.-L. Pan Differential Sensitivity of N- and P/Q-Type Ca2+ Channel Currents to a {micro} Opioid in Isolectin B -Positive and -Negative Dorsal Root Ganglion Neurons J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 939 - 947. [Abstract] [Full Text] [PDF]

				M. Toledo-Rodriguez, B. Blumenfeld, C. Wu, J. Luo, B. Attali, P. Goodman, and H. Markram Correlation Maps Allow Neuronal Electrical Properties to be Predicted from Single-cell Gene Expression Profiles in Rat Neocortex Cereb Cortex, December 1, 2004; 14(12): 1310 - 1327. [Abstract] [Full Text] [PDF]

				C. S. Chan, R. Shigemoto, J. N. Mercer, and D. J. Surmeier HCN2 and HCN1 Channels Govern the Regularity of Autonomous Pacemaking and Synaptic Resetting in Globus Pallidus Neurons J. Neurosci., November 3, 2004; 24(44): 9921 - 9932. [Abstract] [Full Text] [PDF]

				Y.-Q. Yu, Y. Xiong, Y.-S. Chan, and J. He In vivo intracellular responses of the medial geniculate neurones to acoustic stimuli in anaesthetized guinea pigs J. Physiol., October 1, 2004; 560(1): 191 - 205. [Abstract] [Full Text] [PDF]

				A. Agoston, L. Kunz, A. Krieger, and A. Mayerhofer Two Types of Calcium Channels in Human Ovarian Endocrine Cells: Involvement in Steroidogenesis J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4503 - 4512. [Abstract] [Full Text] [PDF]

				N. Leresche, J. Hering, and R. C. Lambert Paradoxical Potentiation of Neuronal T-Type Ca2+ Current by ATP at Resting Membrane Potential J. Neurosci., June 16, 2004; 24(24): 5592 - 5602. [Abstract] [Full Text] [PDF]

				Y. Zhang, A. P. Vilaythong, D. Yoshor, and J. L. Noebels Elevated Thalamic Low-Voltage-Activated Currents Precede the Onset of Absence Epilepsy in the SNAP25-Deficient Mouse Mutant Coloboma J. Neurosci., June 2, 2004; 24(22): 5239 - 5248. [Abstract] [Full Text] [PDF]

				I. Song, D. Kim, S. Choi, M. Sun, Y. Kim, and H.-S. Shin Role of the {alpha}1G T-Type Calcium Channel in Spontaneous Absence Seizures in Mutant Mice J. Neurosci., June 2, 2004; 24(22): 5249 - 5257. [Abstract] [Full Text] [PDF]

				H. Khosravani, C. Altier, B. Simms, K. S. Hamming, T. P. Snutch, J. Mezeyova, J. E. McRory, and G. W. Zamponi Gating Effects of Mutations in the Cav3.2 T-type Calcium Channel Associated with Childhood Absence Epilepsy J. Biol. Chem., March 12, 2004; 279(11): 9681 - 9684. [Abstract] [Full Text] [PDF]

				E. Perez-Reyes Paradoxical Role of T-type Calcium Channels in Coronary Smooth Muscle Mol. Interv., February 1, 2004; 4(1): 16 - 18. [Abstract] [Full Text] [PDF]

				C.-C. Chen, K. G. Lamping, D. W. Nuno, R. Barresi, S. J. Prouty, J. L. Lavoie, L. L. Cribbs, S. K. England, C. D. Sigmund, R. M. Weiss, et al. Abnormal Coronary Function in Mice Deficient in {alpha}1H T-type Ca2+ Channels Science, November 21, 2003; 302(5649): 1416 - 1418. [Abstract] [Full Text] [PDF]

				H. Shan, M. L. Messi, Z. Zheng, Z.-M. Wang, and O. Delbono Preservation of motor neuron Ca2+ channel sensitivity to insulin-like growth factor-1 in brain motor cortex from senescent rat J. Physiol., November 15, 2003; 553(1): 49 - 63. [Abstract] [Full Text] [PDF]

				P. J. Welsby, H. Wang, J. T. Wolfe, R. J. Colbran, M. L. Johnson, and P. Q. Barrett A Mechanism for the Direct Regulation of T-Type Calcium Channels by Ca2+/Calmodulin-Dependent Kinase II J. Neurosci., November 5, 2003; 23(31): 10116 - 10121. [Abstract] [Full Text] [PDF]

				G. Pinato and J. Midtgaard Regulation of Granule Cell Excitability by a Low-Threshold Calcium Spike in Turtle Olfactory Bulb J Neurophysiol, November 1, 2003; 90(5): 3341 - 3351. [Abstract] [Full Text] [PDF]

				A. M. Swensen and B. P. Bean Ionic Mechanisms of Burst Firing in Dissociated Purkinje Neurons J. Neurosci., October 22, 2003; 23(29): 9650 - 9663. [Abstract] [Full Text] [PDF]

				D. Kim, D. Park, S. Choi, S. Lee, M. Sun, C. Kim, and H.-S. Shin Thalamic Control of Visceral Nociception Mediated by T-Type Ca2+ Channels Science, October 3, 2003; 302(5642): 117 - 119. [Abstract] [Full Text] [PDF]

				A. DESTEXHE and T. J. SEJNOWSKI Interactions Between Membrane Conductances Underlying Thalamocortical Slow-Wave Oscillations Physiol Rev, October 1, 2003; 83(4): 1401 - 1453. [Abstract] [Full Text] [PDF]

				J. Mu, W. B. Carden, N. C. Kurukulasuriya, G. M. Alexander, and D. W. Godwin Ethanol Influences on Native T-Type Calcium Current in Thalamic Sleep Circuitry J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 197 - 204. [Abstract] [Full Text] [PDF]

				V. Egger, K. Svoboda, and Z. F. Mainen Mechanisms of Lateral Inhibition in the Olfactory Bulb: Efficiency and Modulation of Spike-Evoked Calcium Influx into Granule Cells J. Neurosci., August 20, 2003; 23(20): 7551 - 7558. [Abstract] [Full Text] [PDF]

				A. T. Schaefer, M. E. Larkum, B. Sakmann, and A. Roth Coincidence Detection in Pyramidal Neurons Is Tuned by Their Dendritic Branching Pattern J Neurophysiol, June 1, 2003; 89(6): 3143 - 3154. [Abstract] [Full Text] [PDF]

				M. Russier, E. Carlier, N. Ankri, L. Fronzaroli, and D. Debanne A-, T-, and H-type Currents Shape Intrinsic Firing of Developing Rat Abducens Motoneurons J. Physiol., May 15, 2003; 549(1): 21 - 36. [Abstract] [Full Text] [PDF]

				R. K. Cloues and W. A. Sather Afterhyperpolarization Regulates Firing Rate in Neurons of the Suprachiasmatic Nucleus J. Neurosci., March 1, 2003; 23(5): 1593 - 1604. [Abstract] [Full Text] [PDF]

				D. M. Porcello, S. D. Smith, and J. R. Huguenard Actions of U-92032, a T-Type Ca2+ Channel Antagonist, Support a Functional Linkage Between IT and Slow Intrathalamic Rhythms J Neurophysiol, January 1, 2003; 89(1): 177 - 185. [Abstract] [Full Text] [PDF]

				E. Perez-Reyes Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels Physiol Rev, January 1, 2003; 83(1): 117 - 161. [Abstract] [Full Text] [PDF]

				J. Chemin, J. Nargeot, and P. Lory Neuronal T-type alpha 1H Calcium Channels Induce Neuritogenesis and Expression of High-Voltage-Activated Calcium Channels in the NG108-15 Cell Line J. Neurosci., August 15, 2002; 22(16): 6856 - 6862. [Abstract] [Full Text] [PDF]

				Y. Zhang, M. Mori, D. L. Burgess, and J. L. Noebels Mutations in High-Voltage-Activated Calcium Channel Genes Stimulate Low-Voltage-Activated Currents in Mouse Thalamic Relay Neurons J. Neurosci., August 1, 2002; 22(15): 6362 - 6371. [Abstract] [Full Text] [PDF]

				K. Hirooka, G. E. Bertolesi, M. E. M. Kelly, E. M. Denovan-Wright, X. Sun, J. Hamid, G. W. Zamponi, A. E. Juhasz, L. W. Haynes, and S. Barnes T-Type Calcium Channel alpha 1G and alpha 1H Subunits in Human Retinoblastoma Cells and Their Loss After Differentiation J Neurophysiol, July 1, 2002; 88(1): 196 - 205. [Abstract] [Full Text] [PDF]

				J.-H. Lee, E.-G. Kim, B.-G. Park, K.-H. Kim, S.-K. Cha, I. D. Kong, J.-W. Lee, and S.-W. Jeong Identification of T-Type alpha 1H Ca2+ Channels (Cav3.2) in Major Pelvic Ganglion Neurons J Neurophysiol, June 1, 2002; 87(6): 2844 - 2850. [Abstract] [Full Text] [PDF]

				J. Wolfart and J. Roeper Selective Coupling of T-Type Calcium Channels to SK Potassium Channels Prevents Intrinsic Bursting in Dopaminergic Midbrain Neurons J. Neurosci., May 1, 2002; 22(9): 3404 - 3413. [Abstract] [Full Text] [PDF]

				H. Su, D. Sochivko, A. Becker, J. Chen, Y. Jiang, Y. Yaari, and H. Beck Upregulation of a T-Type Ca2+ Channel Causes a Long-Lasting Modification of Neuronal Firing Mode after Status Epilepticus J. Neurosci., May 1, 2002; 22(9): 3645 - 3655. [Abstract] [Full Text] [PDF]

				J. Chemin, A. Monteil, E. Perez-Reyes, E. Bourinet, J. Nargeot, and P. Lory Specific contribution of human T-type calcium channel isotypes ({alpha}1G, {alpha}1H and {alpha}1I) to neuronal excitability J. Physiol., April 1, 2002; 540(1): 3 - 14. [Abstract] [Full Text] [PDF]

				J. C. Gomora, A. N. Daud, M. Weiergraber, and E. Perez-Reyes Block of Cloned Human T-Type Calcium Channels by Succinimide Antiepileptic Drugs Mol. Pharmacol., November 1, 2001; 60(5): 1121 - 1132. [Abstract] [Full Text] [PDF]

				O. Lesouhaitier, A. Chiappe, and M. F. Rossier Aldosterone Increases T-Type Calcium Currents in Human Adrenocarcinoma (H295R) Cells by Inducing Channel Expression Endocrinology, October 1, 2001; 142(10): 4320 - 4330. [Abstract] [Full Text] [PDF]

				S. M. Todorovic, V. Jevtovic-Todorovic, S. Mennerick, E. Perez-Reyes, and C. F. Zorumski Cav3.2 Channel Is a Molecular Substrate for Inhibition of T-Type Calcium Currents in Rat Sensory Neurons by Nitrous Oxide Mol. Pharmacol., September 1, 2001; 60(3): 603 - 610. [Abstract] [Full Text] [PDF]

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