 |
||||
|
||||
|
||||
|
||||
|
||||
Previous Article | Next Article
Volume 17, Number 23, Issue of December 1, 1997
Modulation of Rod Photoreceptor Cyclic Nucleotide-Gated Channels by Tyrosine Phosphorylation
Elena Molokanova, Bhavya Trivedi, Alexei Savchenko, and Richard H. Kramer Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida 33101
ABSTRACT
Cyclic nucleotide-gated (CNG) channels in vertebrate photoreceptors are crucial for transducing light-induced changes in cGMP concentration into electrical signals. In this study, we show that both native and exogenously expressed CNG channels from rods are modulated by tyrosine phosphorylation. The cGMP sensitivity of CNG channels, composed of rod
Key words: cGMP; rod outer segment; photoreceptor; phototransduction; tyrosine; protein kinase; protein phosphatase; phosphorylation-subunits expressed in Xenopus oocytes, gradually increases after excision of inside-out patches from the oocyte membrane. This increase in sensitivity is inhibited by a protein tyrosine phosphatase (PTP) inhibitor and is unaffected by three different Ser/Thr phosphatase inhibitors. Moreover, it is suppressed or reversed by application of ATP but not by a nonhydrolyzable ATP analog. Application of protein tyrosine kinase (PTK) inhibitors causes an increase in cGMP sensitivity, but only in the presence of ATP. Taken together, these results suggest that CNG channels expressed in oocytes are associated with active PTK(s) and PTP(s) that regulate their cGMP sensitivity by changing phosphorylation state. The cGMP sensitivity of native CNG channels from salamander rod outer segments also increases and decreases after incubation with inhibitors of PTP(s) and PTK(s), respectively. These results suggest that rod CNG channels are modulated by tyrosine phosphorylation, which may function as a novel mechanism for regulating the sensitivity of rods to light.
INTRODUCTION
Cyclic nucleotide-gated (CNG) channels are crucial for generating electrical signals during phototransduction in vertebrate photoreceptors. Light triggers a decrease in the cytoplasmic concentration of cGMP, causing CNG channels in the plasma membrane to close. The sensitivity of CNG channels to cGMP can be modulated by several intracellular constituents, with important physiological consequences. Intracellular Ca2+ causes a decrease in cGMP sensitivity of rod CNG channels, mediated by direct binding of calmodulin and other Ca2+-binding proteins to the CNG channel protein (Hsu and Molday, 1993
; Gordon et al., 1995a
The cGMP sensitivity of rod CNG channels is also modulated by protein phosphorylation. Gordon et al. (1992)
Recent studies reveal that ion channels can also be modulated by tyrosine phosphorylation (for review, see Siegelbaum, 1994
In this paper, we show that tyrosine phosphorylation is a novel mechanism for modulating rod CNG channels. Rod CNG channels expressed in Xenopus oocytes are associated with active PTK(s) and PTP(s), with phosphorylation or dephosphorylation, respectively, decreasing or increasing their cGMP sensitivity. Moreover, native CNG channels in salamander rod outer segments are also modulated by PTKs and PTPs intrinsic to the retina. We propose that modulation of CNG channels by tyrosine phosphorylation is an important mechanism for controlling the light sensitivity of rods.
MATERIALS AND METHODS
Expression and recording from oocyte CNG channels. A cDNA clone encoding the bovine rod photoreceptor CNG channel) were filled with a solution containing 115 mM NaCl, 5 mM EGTA, and 10 mM HEPES, pH-adjusted to 7.5 with NaOH. This also served as the standard bath solution and cGMP perfusion solution unless noted otherwise. After formation of a gigaohm seal, inside-out patches were excised and the patch pipette was quickly (<30 sec) placed in the outlet of a 1-mm-diameter tube for cGMP application. We used a perfusion manifold containing up to 15 different solutions that is capable of solution changes within 100 msec. A series of four to five cGMP concentrations (10-2000 µM cGMP) was applied to the patch. Application of the series required 20-30 sec and was repeated at 1 min intervals. ATP (Mg salt) was applied at 200 µM and either was present in all solutions and applied continuously (e.g., see Figs. 6, 7) or was applied transiently for 3 min starting 10.5 min after patch excision (e.g., see Figs. 4, 5). Phosphatase and kinase inhibitors were prepared as concentrated stock solutions in water or DMSO, and aqueous solutions containing the final concentrations were prepared for use as needed. The final concentration of DMSO did not exceed 0.1%, which had no effect on CNG channels or their modulation. Sodium pervanadate was prepared as described previously (Wallace, 1995
-S, microcystin-LR, and staurosporine were obtained from Sigma (St. Louis, MO), K252a was obtained from Calbiochem (La Jolla, CA), and okadaic acid, calyculin A, lavendustin A and B, and erbstatin (stable analog) were obtained from LC Laboratories (Woburn, MA).
Fig. 6. Effects of tyrosine kinase inhibitors on CNG channel modulation in oocytes. A, Effect of 10 µM lavendustin A (Lav A). B, Effect of 25 µM erbstatin (Erb) analog on the K1/2 for cGMP activation, both in the presence of continuously applied ATP (200 µM). C, Lack of an effect of lavendustin A. D, Lack of an effect of erbstatin analog, both in the absence of ATP (n = 5-7 patches for each condition).
[View Larger Version of this Image (27K GIF file)]
Fig. 7. Effects of Ser/Thr kinases inhibitors on CNG channel modulation in oocytes. A, Application of staurosporine (100 nM; n = 7). B, Application of K252a (500 nM; n = 11). Both inhibitors were used in the presence of continuously applied ATP (200 µM).
[View Larger Version of this Image (21K GIF file)]
Fig. 4. Effects of continuous exposure to Ser/Thr phosphatase inhibitors on the change in K1/2 in oocyte patches. A, Effect of 250 nM okadaic acid (n = 7). B, Effect of 10 nM calyculin (n = 6). C, Effect of 500 nM microcystin-LR (n = 6). Changes in K1/2 for each inhibitor (filled circles) are plotted along with changes in K1/2 in control solution (open circles; n = 6). All data are normalized to the initial K1/2 (t = 1 min).
[View Larger Version of this Image (29K GIF file)]
Fig. 5. Effects of the tyrosine phosphatase inhibitor vanadate on modulation of CNG channels from oocytes. A, Effect of continuous exposure to 200 µM orthovanadate (open circles; n = 11), 100 µM pervanadate (open squares; n = 5), or neither (filled triangles; n = 34) on changes in K1/2 after patch excision and ATP exposure. B, Effect of pretreatment of intact oocytes (1 hr) with control saline, 200 µM orthovanadate, or 100 µM pervanadate on the initial K1/2 measured 1 min after patch excision (n = 47, 16, and 7, respectively).
[View Larger Version of this Image (30K GIF file)]
Current responses through CNG channels were obtained with an Axopatch 200A patch clamp (Axon Instruments, Foster City, CA), digitized, stored, and later analyzed on a 486 PC using pClamp 6.0 software. Membrane potential was held at 75 mV in all experiments. Current responses were normalized to the maximal CNG current (Imax), which was elicited by saturating cGMP (2 mM). Normalized dose-response curves were fit to the Hill equation: I/Imax = 1/(1 + (K1/2/A)n), where A is the cGMP concentration and n is the Hill coefficient, using a nonlinear least-squares fitting routine (Origin, Microcal Software). Changes in cGMP sensitivity in the presence of drugs were plotted together with matched control results from the same batches of oocytes (i.e., see Figs. 3, 4, 5). Variability among measurements is expressed as mean ± SEM.
Fig. 3. The effects of ATP and its analogs on the time course of the changes of K1/2. A, Changes in K1/2 after patch excision and application of ATP (A1), AMP-PNP (A2), and ATP-
[View Larger Version of this Image (22K GIF file)]
Recording from CNG channels from rod outer segments. Water-phase tiger salamanders (Ambystoma tigranum) maintained in a temperature-controlled aquarium (16°C) on a 12 hr light/dark cycle were used in all experiments at the same time of day. Animals were dark-adapted for 1 hr and anesthetized in an ice-cold solution containing 1 gm/l 2-amino benzoic acid for 20 min before decapitation and removal of eyes under dim red light. Eyes were placed in saline containing (in mM): 155 NaCl, 2.5 KCl, 1 CaCl2, 2 MgCl2, 10 glucose, and 10 HEPES, pH 7.5. A fine Hamilton syringe was used to inject 50 µl of control saline, saline containing 200 µM lavendustin A or B, or saline containing 100 µM Na-pervanadate. After a 2 hr incubation in the dark, retinas were removed under dim illumination and placed in 1 ml of the same saline used for injection for an additional 2 hr in the dark. Finally, after a total of 4 hr of treatment, the retinas were cut into quarters and gently triturated to obtain rod outer segments, which were placed in a recording chamber in the same solution used for eye injection. Borosilicate glass pipettes (3-5 M
RESULTS
This study started with the observation that rod CNG channels in excised patches from Xenopus oocytes gradually increase their sensitivity to cGMP after a patch is excised from the cell. Homomeric CNG channels were expressed in oocytes by injecting mRNA encoding the-subunits (Chen et al., 1993
After obtaining an excised patch containing homomeric CNG channels, various concentrations (10-2000 µM) of cGMP were applied repeatedly at 1-2 min intervals. Figures 1 and 2 show changes in cGMP sensitivity of CNG channels from one representative patch. Current responses to subsaturating cGMP concentrations (e.g., 10-250 µM) increased during the first 10 min after excision, whereas the response to saturating cGMP (2000 µM cGMP) did not change (Fig. 1A,B). After 10 min, the cytoplasmic side of the patch was exposed to 200 µM ATP for 3 min. Then the ATP was washed away and cGMP responses were elicited again. The transient exposure to ATP led to a decrease in the response to subsaturating cGMP concentrations without affecting the saturating response (Fig. 1C). 
Fig. 1. Modulation of current through CNG channels in an excised patch from a Xenopus oocyte. Currents were elicited by application of cGMP at concentrations of 50, 100, 250, and 2000 µM 1 and 10 min after excision, and after a 3 min application of 200 µM ATP (13.5 min after excision).
[View Larger Version of this Image (11K GIF file)]
Fig. 2. Change in cGMP sensitivity of CNG channels in an excised patch from an oocyte. A, Dose-response curves of CNG channel activation by cGMP, with data taken from Figure 1. Solid curves show the fit to the Hill equation. B, Changes in K1/2, but not the Hill coefficient or maximal current, with time after patch excision and after ATP application. This figure shows an analysis of dose-response data from a single patch collected at 1 min intervals.
[View Larger Version of this Image (22K GIF file)]
Dose-response curves show that less cGMP is required to activate the CNG channels 10 min after patch excision than 1 min after excision, whereas the maximal current does not change (Fig. 2A). Transient ATP application leads to an opposite change, decreasing the cGMP sensitivity. To analyze these effects further, each of the repeated dose-response curves was fit with the Hill equation, and the free parameters (K1/2, Hill coefficient, and maximal current) were plotted over time. Figure 2B shows that the Hill coefficient and the maximal current did not change with time and were unaffected by ATP. However, the K1/2 decreased from 119 to 54 µM over the first 10 min and then stabilized, exhibiting no further spontaneous changes. However, transient application of ATP caused the K1/2, measured immediately after ATP exposure, to increase to 85 µM. Subsequently, the K1/2 again decreased to 55 µM with a time constant ( ) of 1.7 min, similar to that observed for the decrease in K1/2 after excision (
To investigate whether ATP is used as a substrate in a phosphorylation reaction, we compared its effects with those of two ATP analogs that differ from ATP in their ability to phosphorylate proteins. Data from multiple patches were normalized such that the K1/2 of the first dose-response curve after excision (1 min) was set to 1.0. Whereas transient application of ATP increased the K1/2 by ~37% (Fig. 3A1), application of the nonhydrolyzable ATP analog adenylyl-imidodiphosphate (AMP-PNP) had no effect (Fig. 3A2). Application of ATP- -O-(3
We also examined the effect of continuous application of ATP from the moment the patch was excised (Fig. 3B). Continuous exposure to ATP greatly reduced the spontaneous change in K1/2, such that 10 min after excision the K1/2 was 88% of the initial K1/2 compared with control patches (ATP-free), in which the K1/2 dropped to 52% after 10 min. Taken together with our ATP analog experiments, these results suggest that ATP is a substrate in a phosphorylation reaction that opposes or reverses the spontaneous decrease in K1/2.
We propose that the following scenario accounts for the changes in sensitivity of CNG in oocyte patches. The cGMP sensitivity of CNG channels (or a closely associated regulator protein) is modulated by phosphorylation, with cGMP sensitivity being low in the phosphorylated state and high in the dephosphorylated state. The oocyte patch contains active protein phosphatase(s) and protein kinase(s) that remain associated with the membrane after patch excision. In the absence of ATP, the kinase cannot catalyze phosphorylation; thus, the phosphatase dephosphorylates the channels within 10 min after excising the patch, increasing cGMP sensitivity. In the presence of ATP, both the kinase and the phosphatase are active, more closely maintaining the initial phosphorylation state. Thus, in the presence of ATP, the sensitivity of the CNG channels reflects a balance between phosphorylation and dephosphorylation, similar to the situation in the intact cell. In the following experiments, we use phosphatase and kinase inhibitors to test this hypothesis. Effects of phosphatase inhibitors
To determine whether Ser/Thr dephosphorylation is involved in the increase in CNG channel sensitivity in oocyte patches, we applied three selective inhibitors of Ser/Thr phosphatases: okadaic acid, calyculin A, and microcystin-LR (Cohen, 1989
We next asked whether inhibitors selective for tyrosine phosphatases could inhibit the decrease in K1/2. Orthovanadate (Swarup et al., 1982
To test whether such a phosphatase might regulate the sensitivity of CNG channels to cGMP in intact oocytes, cells were pretreated with 100 µM pervanadate, which is membrane-permeant, for 1 hr before obtaining an excised patch (Fig. 5B). Patches from pervanadate-treated oocytes had an initial K1/2 (measured at 1 min after excision) of 184 ± 18 µM, significantly higher than that exhibited by untreated oocytes (117 ± 6 µM). Pretreatment with orthovanadate, which is not membrane-permeant, caused a small but significant increase in K1/2 to 134 ± 6 µM. However, this may result from the effect of orthovanadate during the first minute after excision, before the initial K1/2 could be measured. Effects of kinase inhibitors
To test whether the effect of ATP on the cGMP sensitivity of CNG channels is attributable to phosphorylation, we first used selective inhibitors of protein tyrosine kinases. Figure 6, A and B, shows the effects of lavendustin A (Onoda et al., 1989
We also tested whether inhibitors of Ser/Thr kinase inhibitors affect the sensitivity of CNG channels to cGMP. Staurosporine, an inhibitor of several Ser/Thr kinases including protein kinase C and cAMP-dependent protein kinase (Ruegg and Burgess, 1989 Experiments on native rod CNG channels
Our experiments on rod CNG channels expressed in oocytes show that PTKs and PTPs in the oocyte membrane can modulate the channels. Are native CNG channels in rod outer segments also modulated by tyrosine phosphorylation? Unlike our findings with oocytes, spontaneous increases in cGMP affinity in CNG channels from rod outer segments fail to occur in very low-Ca2+ solutions (<107 M) (Gordon et al., 1992
Therefore, to examine the possible effect of tyrosine phosphorylation of the native CNG channels, we applied tyrosine kinase or phosphatase inhibitors to intact rods for a longer time (3.5-4.0 hr). Eyes dissected from tiger salamanders (Ambystoma tigranum) were injected with 50 µl of a solution containing lavendustin A, lavendustin B (an inactive analog), pervanadate, or control saline. After 2 hr, retinas were removed and incubated for an additional 2 hr in the same solutions. Then outer segments were isolated and patch-clamp experiments were begun to obtain inside-out patches. Figure 8 shows the initial K1/2 (1 min after excision) of CNG channels from each group of rods. Patches from lavendustin A-treated rods had CNG channels with a K1/2 of 14 ± 1 µM, whereas patches from pervanadate-treated rods had CNG channels with a K1/2 of 32 ± 2 µM, both significantly different (p < 0.05 and p < 0.01, respectively) than patches from control rods (K1/2 = 23 ± 2 µM). The K1/2 of channels from lavendustin B-treated rods was 23 ± 1 µM, not significantly different from control. 
Fig. 8. Effects of PTK and PTP inhibitors on native CNG channels. K1/2 of cGMP activation was measured 1 min after excision of patches from rod outer segments from tiger salamander retina. Rods were exposed to control saline (n = 5), 100 µM pervanadate (n = 7), 10 µM lavendustin A (n = 7), or 10 µM lavendustin B (n = 4) for 3.5-4.0 hr before patch excision. cGMP test solutions were with or without added IBMX (100 µM) as indicated (n = 4 patches for each).
[View Larger Version of this Image (25K GIF file)]
Patches excised from rod outer segments can retain elements of the phototransduction cascade, including rhodopsin, transducin, and cGMP phosphodiesterase (PDE) (Ertel, 1989). The apparent affinity of CNG channels in these patches can be underestimated because active PDE can reduce the concentration of cGMP reaching the channels (R. Kramer and S. Nawy, unpublished observations). To rule out the possibility that modulation of PDE activity, rather than modulation of CNG channels, underlies differences in the apparent affinity of rod CNG channels exposed to lavendustin A or pervanadate, the initial K1/2 was measured in some experiments in the presence of 100 µM isobutylmethylxanthine (IBMX), which blocks PDE. Even with IBMX present, the lavendustin A-treated rods had CNG channels that were twice as sensitive to cGMP (K1/2 = 16 ± 2 µM) than CNG channels from pervanadate-treated rods (K1/2 = 37 ± 5 µM).
Thus, it appears that enhancing dephosphorylation by inhibiting tyrosine kinase results in channels with a high sensitivity to cGMP, whereas enhancing phosphorylation by inhibiting tyrosine phosphatase results in channels with a low sensitivity to cGMP. It should be noted that the magnitude and the direction of the change in apparent affinity brought about by phosphorylation are similar for CNG channels from rods and from oocytes; tyrosine phosphorylation results in an approximately twofold decrease in cGMP sensitivity.
DISCUSSION
Our results suggest that the cGMP sensitivity of rod CNG channels expressed in Xenopus oocytes is modulated by active PTKs and PTPs that remain associated with the channels in excised patches for many minutes after excision. The modulation of CNG channels may involve direct tyrosine phosphorylation of the channel protein(s), or it may be indirect, with tyrosine phosphorylation occurring on unidentified proteins that may be closely associated with CNG channels. Although this remains a possibility, there is a growing body of electrophysiological and biochemical evidence that suggests that signaling complexes containing closely associated kinases, phosphatases, and channels are common for many channels in many cell types (see Reinhart and Levitan, 1995
Do CNG channels contain specific sequences that mediate interactions with PTPs or PTKs? Recent studies of a specific K+ channel (Kv1.5) have shown that it contains a proline-rich consensus sequence that mediates association with SH3 domains in the PTK v-Src (Holmes et al., 1996b
Our results show that transient ATP application only partially reverses the increase in cGMP sensitivity after excision of patches from oocytes (Fig. 3A1) and that continuous ATP application only partially suppresses the increase in sensitivity (Fig. 3B). In addition, the cGMP sensitivity of CNG channels treated with tyrosine kinases inhibitors only partially recovers after these inhibitors are removed, even though ATP is present (Fig. 6A,B). We propose that the following scenario accounts for the observed partial effects of ATP: After excision, the rate of phosphorylation is slower than that of dephosphorylation, such that a new equilibrium is reached, with a net decrease in phosphorylation, even in the presence of ATP. The change in phosphorylation/dephosphorylation rates after excision could result from wash-out, either of some regulatory factor of either the kinase or the phosphatase,or wash-out of the kinase itself. Because the kinase cannot keep up with the phosphatase, addition of ATP cannot restore the original sensitivity of the channel.
Modulation of native rod CNG channels is more complex than modulation of the expressed homomeric channels, with both Ser/Thr phosphorylation and tyrosine phosphorylation decreasing the sensitivity to cGMP. Ca2+-dependent Ser/Thr phosphatases increase the cGMP sensitivity of rod CNG channels in excised patches (Gordon et al., 1992
The rate of decrease in K1/2 is accelerated when the channels are opened with cGMP. In addition, the decrease in cGMP sensitivity after ATP application can be prevented by opening the channels with saturating cGMP (E. Molokanova and R. H. Kramer, unpublished observations). Therefore, modulation mediated by phosphorylation/dephosphorylation is dependent on the open/closed state of the channel, strongly implying that modulation involves phosphorylation of the CNG channel itself. In particular, these observations suggest that either cGMP occupancy of its binding sites or the conformational change associated with channel opening (or both) alters the accessibility of the tyrosine phosphorylation site(s) to PTKs and PTPs. The conserved cyclic nucleotide binding domain of the
The PTPs and PTKs that regulate rod CNG channels may be active independent of extracellular ligands (such as v-Src), or they may be receptor-activated. Rod outer segments contain several types of growth factor receptors that exhibit PTK activity in the presence of the appropriate ligands. Most notably, receptors for insulin-like growth factor-1 (IGF-1) are found in high density in rod outer segments and can elicit tyrosine phosphorylation of the G-protein transducin (Zick et al., 1987
In conclusion, we have shown that the sensitivity of rod CNG channels to cGMP is modulated by tyrosine phosphorylation. Our results raise many intriguing questions about the site of tyrosine phosphorylation, the intracellular and extracellular signals that regulate PTKs and PTPs in rods, and the impact of tyrosine phosphorylation on the light response. Thus, despite having achieved a detailed and advanced understanding of the complexity of phototransduction, our results demonstrate that new levels of biochemical modulation of the signaling cascade continue to be discovered.
FOOTNOTES
Received July 8, 1997; revised Sept. 19, 1997; accepted Sept. 23, 1997.
This work was supported by grants from National Institutes of Health (NS 30695) and the American Heart Association, Florida Affiliate (9502002) to R.H.K. B.T. is a Howard Hughes Medical Institute Predoctoral Fellow. We thank Dr. Scott Nawy for advice and comments on this manuscript.
Correspondence should be addresses to Dr. Richard H. Kramer, P.O. Box 016189, University of Miami School of Medicine, Miami, FL 33101.
REFERENCES
- Aniksztejn L, Catarsi S, Drapeau P (1997) Channel modulation by tyrosine phosphorylation in an identified leech neuron. J Physiol (Lond) 498:135-142
[Abstract/Free Full Text] .- Cassidy P, Hoar PE, Kerrick WG (1979) Irreversible thiophosphorylation and activation of tension in functionally skinned rabbit ileum strips by [35S]ATP-
[Abstract/Free Full Text] .- Chen J, Martin BL, Brautigan DL (1992) Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science 257:1261-1264
[Abstract/Free Full Text] .- Chen T-Y, Peng Y-W, Dhallan RS, Ahamed B, Reed RR, Yau K-W (1993) A new subunit of the cyclic nucleotide-gated cation channel in retinal rods. Nature 362:764-767[Medline].
- Cohen P (1989) Structure and regulation of protein phosphatases. Annu Rev Biochem 58:453-508[Web of Science][Medline].
- Ertel EA (1990) Excised patches of plasma membrane from vertebrate rod outer segments retain a functional phototransduction enzymatic cascade. Proc Natl Acad Sci USA 87:4226-4230
[Abstract/Free Full Text] .- Fuhrer C, Hall ZW (1996) Functional interaction of Src family kinases with the acetylcholine receptor in C2 myocytes. J Biol Chem 271:32474-32481
[Abstract/Free Full Text] .- Gordon SE, Brautigan DL, Zimmerman AL (1992) Protein phosphatases modulate the apparent agonist affinity of the light-regulated ion channel in retinal rods. Neuron 9:739-748[Web of Science][Medline].
- Gordon SE, Downing-Park J, Zimmerman AL (1995a) Modulation of the cGMP-gated ion channel in frog rods by calmodulin and an endogenous inhibitory factor. J Physiol (Lond) 486:533-546
[Abstract/Free Full Text] .- Gordon SE, Downing-Park J, Tam B, Zimmerman AL (1995b) Diacylglycerol analogs inhibit the rod cGMP-gated channel by a phosphorylation-independent mechanism. Biophys J 69:409-417[Web of Science][Medline].
- Heffetz D, Bushkin I, Dror R, Zick Y (1990) The insulomimetic agents H2O2 and vanadate stimulate protein tyrosine phosphorylation in intact cells. J Biol Chem 265:2896-2902
[Abstract/Free Full Text] .- Holmes TC, Fadool DA, Levitan IB (1996a) Tyrosine phosphorylation of the Kv13 potassium channel. J Neurosci 16:1581-1590
[Abstract/Free Full Text] .- Holmes TC, Fadool DA, Ren R, Levitan IB (1996b) Association of Src tyrosine kinase with a human potassium channel mediated by SH3 domain. Science 274:2089-2091
[Abstract/Free Full Text] .- Hunter T (1995) Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell 80:225-236[Web of Science][Medline].
- Hsu YT, Molday RS (1993) Modulation of the cGMP-gated channel in rod photoreceptor cells by calmodulin. Nature 361:76-79[Medline].
- Huang X-Y, Morelli AD, Peralta EG (1993) Tyrosine kinase-dependent suppression of a potassium channel by the G1 protein-coupled muscarinic receptor. Cell 75:1145-1156[Web of Science][Medline].
- Ildefonse M, Crouzy S, Bennett N (1992) Gating of retinal rod cation channel by different nucleotides: comparative study of unitary channels. J Membr Biol 130:91-104[Web of Science][Medline].
- Jonas EA, Knox RJ, Kaczmarek LK, Schwartz JH, Solomon DH (1996) Insulin receptor in Aplysia neurons: characterization, molecular cloning, and modulation of ion currents. J Neurosci 16:1645-1658
[Abstract/Free Full Text] .- Karpen JW, Brown RL, Stryer L, Baylor DA (1993) Interactions between divalent cations and the gating machinery of cyclic GMP-activated channels in salamander retinal rods. J Gen Physiol 101:1-25
[Abstract/Free Full Text] .- Kaupp BU, Niidome T, Tanabe T, Terada S, Bonigk W, Stuhmer W, Cook NJ, Kangawa K, Matsuo H, Hirode T, Miyata T, Numa S (1989) Primary structure and functional expression from complementary DNA of the rod photoreceptor cGMP-gated channel. Nature 342:762-766[Medline].
- Koerschen HG, Illing M, Seifert R, Sesti F, Williams A, Gotzes S, Colville C, Muller F, Dose A, Godde M, Molday L, Kaupp UB, Molday RS (1995) A 240 kDa protein represents the complete beta subunit of the cyclic nucleotide-gated channel from rod photoreceptor. Neuron 15:627-636[Web of Science][Medline].
- MacKintosh C, Beattie KA, Klumpp S, Cohen P, Cod GA (1990) Cyanobacterial microcystin-LR is a potent and specific inhibitor of protein phosphatases 1 and 2A from both mammals and higher plants. FEBS Lett 264:187-192[Web of Science][Medline].
- Mascarelli F, Raulais D, Courtois Y (1989) Fibroblast growth factor phosphorylation and receptors in rod outer segments. EMBO J 8:2265-2273[Web of Science][Medline].
- Moss SJ, Gorrie GH, Amato A, Smart TG (1995) Modulation of GABAA receptors by tyrosine phosphorylation. Nature 377:344-348[Medline].
- Nakatani K, Koutalis Y, Yau K-W (1995) Ca2+ modulation of the cGMP-gated channels of bullfrog retinal rod photoreceptors. J Physiol (Lond) 484:69-76
[Abstract/Free Full Text] .- Onoda T, Iinuma H, Sasaki Y, Hamada M, Isshiki K, Naganama H, Takeuchi T, Tatsuta K, Umezawa K (1989) Isolation of a novel tyrosine kinase inhibitor, lavendustin A, from Streptomyces griseolavendus. J Nat Prod 52:1252-1257[Medline].
- Reinhart PH, Levitan IB (1995) Kinase and phosphatase activities intimately associated with a reconstituted calcium-dependent potassium channel. J Neurosci 15:4572-4579[Abstract].
- Ruegg UT, Burgess GM (1989) Staurosporine, K252a and UCN-01: potent but nonspecific inhibitors of protein kinases. Trends Pharmacol Sci 10:218-222[Medline].
- Siegelbaum SA (1994) Ion channel control by tyrosine phosphorylation. Curr Biol 4:242-245[Web of Science][Medline].
- Swarup G, Cohen S, Garbers DL (1982) Inhibition of membrane phosphotyrosyl-protein phosphatase activity by vanadate. Biochem Biophys Res Commun 107:1104-1109[Web of Science][Medline].
- Swope SL, Huganir RL (1993) Molecular cloning of two abundant protein tyrosine kinases in Torpedo electric organ that associate with the acetylcholine receptor. J Biol Chem 268:25152-25161
[Abstract/Free Full Text] .- Swope SL, Huganir RL (1994) Binding of the nicotinic acetylcholine receptor to SH2 domains of Fyn and Fyk protein tyrosine kinases. J Biol Chem 269:29817-29824
[Abstract/Free Full Text] .- Tapley P, Lamballe F, Barbacid M (1992) K252a is a selective inhibitor of the tyrosine protein kinase activity of the trk family of oncogenes and neurotrophin receptors. Oncogene 7:371-381[Web of Science][Medline].
- Umezawa K, Hori T, Tajima H, Imoto M, Isshiki K, Takeuchi T (1990) Inhibition of epidermal growth factor-induced DNA synthesis by tyrosine kinase inhibitors. FEBS Lett 260:198-200[Web of Science][Medline].
- Waldbillig RJ, Pfeffer BA, Schoen TJ, Adler AA, Shen-Orr Z, Scavo L, LeRoith D, Chader GJ (1991) Evidence for an insulin-like growth factor autocrine-paracrine system in the retinal photoreceptor-pigment epithelial cell complex. J Neurochem 57:1522-1533[Web of Science][Medline].
- Wallace BG (1995) Regulation of the interaction of nicotinic acetylcholine receptors with the cytoskeleton by agrin-activated protein tyrosine kinase. J Cell Biol 128:1121-1129
[Abstract/Free Full Text] .- Wang YT, Yu XM, Salter MW (1996) Ca2+-independent reduction of N-methyl-D-aspartate channel activity by protein tyrosine phosphatase. Proc Natl Acad Sci USA 93:1721-1725
[Abstract/Free Full Text] .- Wilson GF, Kaczmarek LK (1993) Mode-switching of a voltage-gated cation channel is mediated by a protein kinase-A regulated tyrosine phosphatase. Nature 366:433-438[Medline].
- Xiong Z, Cheung DW (1995) ATP-dependent inhibition of Ca2+-activated K+ channels in vascular smooth muscle cells by neuropeptide Y. Pflügers Arch 431:110-116[Web of Science][Medline].
- Yu X-M, Askalan R, Keil GJ, Salter MW (1997) NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science 275:674-678
[Abstract/Free Full Text] .- Zick Y, Spiegel AM, Sagi-Eisenberg R (1987) Insulin-like growth factor I receptors in retinal rod outer segments. J Biol Chem 262:10259-10264
[Abstract/Free Full Text] .
Copyright ©1997 Society for Neuroscience 0270-6474/1997/179068-09$05.00/0
This article has been cited by other articles:
D.-G. Luo, T. Xue, and K.-W. Yau
How vision begins: An odyssey
PNAS, July 22, 2008; 105(29): 9855 - 9862.
[Abstract] [Full Text] [PDF]
S.-K. Chen, G. Y.-P. Ko, and S. E. Dryer
Somatostatin Peptides Produce Multiple Effects on Gating Properties of Native Cone Photoreceptor cGMP-Gated Channels That Depend on Circadian Phase and Previous Illumination
J. Neurosci., November 7, 2007; 27(45): 12168 - 12175.
[Abstract] [Full Text] [PDF]
K.-S. Chae, G. Y.-P. Ko, and S. E. Dryer
Tyrosine Phosphorylation of cGMP-Gated Ion Channels Is under Circadian Control in Chick Retina Photoreceptors
Invest. Ophthalmol. Vis. Sci., February 1, 2007; 48(2): 901 - 906.
[Abstract] [Full Text] [PDF]
S. R. Bright, E. D. Rich, and M. D. Varnum
Regulation of Human Cone Cyclic Nucleotide-Gated Channels by Endogenous Phospholipids and Exogenously Applied Phosphatidylinositol 3,4,5-trisphosphate
Mol. Pharmacol., January 1, 2007; 71(1): 176 - 183.
[Abstract] [Full Text] [PDF]
Q. He, D. Alexeev, M. E. Estevez, S. L. McCabe, P. D. Calvert, D. E. Ong, M. C. Cornwall, A. L. Zimmerman, and C. L. Makino
Cyclic Nucleotide-gated Ion Channels in Rod Photoreceptors Are Protected from Retinoid Inhibition
J. Gen. Physiol., October 1, 2006; 128(4): 473 - 485.
[Abstract] [Full Text] [PDF]
D. M. Horrigan, M. L. Tetreault, N. Tsomaia, C. Vasileiou, B. Borhan, D. F. Mierke, R. K. Crouch, and A. L. Zimmerman
Defining the Retinoid Binding Site in the Rod Cyclic Nucleotide-gated Channel
J. Gen. Physiol., October 31, 2005; 126(5): 453 - 460.
[Abstract] [Full Text] [PDF]
L. Hua and S. E. Gordon
Functional Interactions Between A' Helices in the C-linker of Open CNG Channels
J. Gen. Physiol., February 28, 2005; 125(3): 335 - 344.
[Abstract] [Full Text] [PDF]
J. P. Johnson Jr. and W. N. Zagotta
The carboxyl-terminal region of cyclic nucleotide-modulated channels is a gating ring, not a permeation path
PNAS, February 22, 2005; 102(8): 2742 - 2747.
[Abstract] [Full Text] [PDF]
M. C. Trudeau and W. N. Zagotta
Dynamics of Ca2+-Calmodulin-dependent Inhibition of Rod Cyclic Nucleotide-gated Channels Measured by Patch-clamp Fluorometry
J. Gen. Physiol., August 30, 2004; 124(3): 211 - 223.
[Abstract] [Full Text] [PDF]
S. L. McCabe, D. M. Pelosi, M. Tetreault, A. Miri, W. Nguitragool, P. Kovithvathanaphong, R. Mahajan, and A. L. Zimmerman
All-trans-retinal Is a Closed-state Inhibitor of Rod Cyclic Nucleotide-gated Ion Channels
J. Gen. Physiol., April 26, 2004; 123(5): 521 - 531.
[Abstract] [Full Text] [PDF]
T. Rosenbaum, A. Gordon-Shaag, L. D. Islas, J. Cooper, M. Munari, and S. E. Gordon
State-dependent Block of CNG Channels by Dequalinium
J. Gen. Physiol., February 23, 2004; 123(3): 295 - 304.
[Abstract] [Full Text] [PDF]
J. L. Krajewski, C. W. Luetje, and R. H. Kramer
Tyrosine Phosphorylation of Rod Cyclic Nucleotide-Gated Channels Switches Off Ca2+/Calmodulin Inhibition
J. Neurosci., November 5, 2003; 23(31): 10100 - 10106.
[Abstract] [Full Text] [PDF]
E. Molokanova, J. L Krajewski, D. Satpaev, C. W Luetje, and R. H Kramer
Subunit contributions to phosphorylation-dependent modulation of bovine rod cyclic nucleotide-gated channels
J. Physiol., October 15, 2003; 552(2): 345 - 356.
[Abstract] [Full Text] [PDF]
C. Peng, E. D. Rich, C. A. Thor, and M. D. Varnum
Functionally Important Calmodulin-binding Sites in Both NH2- and COOH-terminal Regions of the Cone Photoreceptor Cyclic Nucleotide-gated Channel CNGB3 Subunit
J. Biol. Chem., June 27, 2003; 278(27): 24617 - 24623.
[Abstract] [Full Text] [PDF]
G. Y.-P. Ko, M. L. Ko, and S. E. Dryer
Circadian Phase-Dependent Modulation of cGMP-Gated Channels of Cone Photoreceptors by Dopamine and D2 Agonist
J. Neurosci., April 15, 2003; 23(8): 3145 - 3153.
[Abstract] [Full Text] [PDF]
T. Rosenbaum, L. D. Islas, A. E. Carlson, and S. E. Gordon
Dequalinium: A Novel, High-affinity Blocker of CNGA1 Channels
J. Gen. Physiol., December 30, 2002; 121(1): 37 - 47.
[Abstract] [Full Text] [PDF]
M. Holmgren
Influence of Permeant Ions on Gating in Cyclic Nucleotide-gated Channels
J. Gen. Physiol., December 30, 2002; 121(1): 61 - 72.
[Abstract] [Full Text] [PDF]
C.-H. Cheng, D. T.-W. Yew, H.-Y. Kwan, Q. Zhou, Y. Huang, Y. Liu, W.-Y. Chan, and X. Yao
An Endogenous RNA Transcript Antisense to CNGalpha 1 Cation Channel mRNA
Mol. Biol. Cell, October 1, 2002; 13(10): 3696 - 3705.
[Abstract] [Full Text] [PDF]
U. B. Kaupp and R. Seifert
Cyclic Nucleotide-Gated Ion Channels
Physiol Rev, July 1, 2002; 82(3): 769 - 824.
[Abstract] [Full Text] [PDF]
D. M. Dean, W. Nguitragool, A. Miri, S. L. McCabe, and A. L. Zimmerman
All-trans-retinal shuts down rod cyclic nucleotide-gated ion channels: A novel role for photoreceptor retinoids in the response to bright light?
PNAS, June 11, 2002; 99(12): 8372 - 8377.
[Abstract] [Full Text] [PDF]
G. M. Yanochko and A. J. Yool
Regulated Cationic Channel Function in Xenopus Oocytes Expressing Drosophila Big Brain
J. Neurosci., April 1, 2002; 22(7): 2530 - 2540.
[Abstract] [Full Text] [PDF]
R. V. S. Rajala and R. E. Anderson
Interaction of the Insulin Receptor {beta}-Subunit with Phosphatidylinositol 3-Kinase in Bovine ROS
Invest. Ophthalmol. Vis. Sci., December 1, 2001; 42(13): 3110 - 3117.
[Abstract] [Full Text] [PDF]
M. J. Davis, X. Wu, T. R. Nurkiewicz, J. Kawasaki, P. Gui, M. A. Hill, and E. Wilson
Regulation of ion channels by protein tyrosine phosphorylation
Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1835 - H1862.
[Abstract] [Full Text] [PDF]
A. Savchenko, T. W. Kraft, E. Molokanova, and R. H. Kramer
Growth factors regulate phototransduction in retinal rods by modulating cyclic nucleotide-gated channels through dephosphorylation of a specific tyrosine residue
PNAS, April 18, 2001; (2001) 101524998.
[Abstract] [Full Text]
F. Muller, M. Vantler, D. Weitz, E. Eismann, M. Zoche, K.-W. Koch, and U B. Kaupp
Ligand sensitivity of the {alpha}2 subunit from the bovine cone cGMP-gated channel is modulated by protein kinase C but not by calmodulin
J. Physiol., April 15, 2001; 532(2): 399 - 409.
[Abstract] [Full Text] [PDF]
R. H. Kramer and E. Molokanova
Modulation of cyclic-nucleotide-gated channels and regulation of vertebrate phototransduction
J. Exp. Biol., January 9, 2001; 204(17): 2921 - 2931.
[Abstract] [Full Text] [PDF]
G. Y.-P. Ko, M. L. Ko, and S. E. Dryer
Developmental Expression of Retinal Cone cGMP-Gated Channels: Evidence for Rapid Turnover and Trophic Regulation
J. Neurosci., January 1, 2001; 21(1): 221 - 229.
[Abstract] [Full Text] [PDF]
S. Okubo, N. L. Bernardo, G. T. Elliott, M. L. Hess, and R. C. Kukreja
Tyrosine kinase signaling in action potential shortening and expression of HSP72 in late preconditioning
Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2269 - H2276.
[Abstract] [Full Text] [PDF]
K. B. Womack, S. E. Gordon, F. He, T. G. Wensel, C.-C. Lu, and D. W. Hilgemann
Do Phosphatidylinositides Modulate Vertebrate Phototransduction?
J. Neurosci., April 15, 2000; 20(8): 2792 - 2799.
[Abstract] [Full Text] [PDF]
T. L. Anthony, H. L. Brooks, D. Boassa, S. Leonov, G. M. Yanochko, J. W. Regan, and A. J. Yool
Cloned Human Aquaporin-1 Is a Cyclic GMP-Gated Ion Channel
Mol. Pharmacol., March 1, 2000; 57(3): 576 - 588.
[Abstract] [Full Text]
E. Molokanova, F. Maddox, C. W. Luetje, and R. H. Kramer
Activity-Dependent Modulation of Rod Photoreceptor Cyclic Nucleotide-Gated Channels Mediated by Phosphorylation of a Specific Tyrosine Residue
J. Neurosci., June 15, 1999; 19(12): 4786 - 4795.
[Abstract] [Full Text] [PDF]
J. Li and H. A. Lester
Functional Roles of Aromatic Residues in the Ligand-Binding Domain of Cyclic Nucleotide-Gated Channels
Mol. Pharmacol., May 1, 1999; 55(5): 873 - 882.
[Abstract] [Full Text]
J. Li and H. A. Lester
Single-Channel Kinetics of the Rat Olfactory Cyclic Nucleotide-Gated Channel Expressed in Xenopus Oocytes
Mol. Pharmacol., May 1, 1999; 55(5): 883 - 893.
[Abstract] [Full Text]
E. Wischmeyer, F. Doring, and A. Karschin
Acute Suppression of Inwardly Rectifying Kir2.1 Channels by Direct Tyrosine Kinase Phosphorylation
J. Biol. Chem., December 18, 1998; 273(51): 34063 - 34068.
[Abstract] [Full Text] [PDF]
A. J. Ghalayini, N. Desai, K. R. Smith, R. M. Holbrook, M. H. Elliott, and H. Kawakatsu
Light-dependent Association of Src with Photoreceptor Rod Outer Segment Membrane Proteins in Vivo
J. Biol. Chem., January 4, 2002; 277(2): 1469 - 1476.
[Abstract] [Full Text] [PDF]
R. M. Law, A. Stafford, and M. W. Quick
Functional Regulation of gamma -Aminobutyric Acid Transporters by Direct Tyrosine Phosphorylation
J. Biol. Chem., July 28, 2000; 275(31): 23986 - 23991.
[Abstract] [Full Text] [PDF]
A. Savchenko, T. W. Kraft, E. Molokanova, and R. H. Kramer
Growth factors regulate phototransduction in retinal rods by modulating cyclic nucleotide-gated channels through dephosphorylation of a specific tyrosine residue
PNAS, May 8, 2001; 98(10): 5880 - 5885.
[Abstract] [Full Text] [PDF]
This Article Abstract 
Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager 
Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (80) Citing Articles via Google Scholar Google Scholar Articles by Molokanova, E. Articles by Kramer, R. H. Search for Related Content PubMed PubMed Citation Articles by Molokanova, E. Articles by Kramer, R. H.
ABSTRACT
|
|
|
|
 |
|