T-Type Calcium Channels in Cones
Adam Davison, Uwe Thorsten Lux, Johann Helmut Brandstätter, Norbert Babai
(see pages 6325–6343)
Cone photoreceptors are hyperpolarized in light and become depolarized as the light dims. The depolarization spreads passively to the axon terminal, where it causes voltage-activated calcium channels to open, triggering a graded increase in vesicle release. High-voltage-activated (HVA) L-type calcium channels, particularly CaV1.4 channels, have been identified as the main calcium channels in cones, but synaptic vesicle release persists in mice expressing mutant versions of these channels, suggesting that additional voltage-activated calcium channels are present. Davison, Lux, et al. provide evidence that these channels are low-voltage-activated (LVA) T-type calcium channels.
Calcium currents in cone axon terminals were recorded during membrane depolarization in the presence of potassium-channel and glutamate-receptor blockers. Ramping voltage from a strongly hyperpolarized membrane potential produced two current peaks—at approximately –40 mV and approximately –20 mV—suggesting the presence of both LVA and HVA calcium channels. Importantly, a selective blocker of T-type calcium channels reduced the low-voltage peak, whereas a selective blocker of L-type channels reduced the high-voltage peak without affecting the low-voltage peak. Furthermore, the activation and inactivation kinetics of the LVA current were similar to those previously described for T-type channels, and RT-PCR indicated that CaV3.2 T-type calcium channels were expressed in cones.
Like in other cell types, T-type LVA channels in cones contributed to calcium spike-like events that occurred in dark-adapted retinas, especially after flashes of light. T-type channels also contributed to synaptic vesicle release: estimates based on capacitance measurements indicated that ∼41% fewer vesicles were released by a depolarizing pulse when T-type channels were largely inactivated. Moreover, activation of L-type channels triggered the release of more vesicles when T-type channels were available than when they were inactivated.
These results suggest that both L- and T-type calcium channels contribute to synaptic vesicle release from cones. Notably, the LVA channels began to open at membrane potentials typical of dark-adapted retinas, whereas HVA channels became activated at more depolarized potentials. This suggests that when the light dims, T-channels open, leading to greater depolarization, which opens L-type channels, leading to the production of calcium spikes. Thus, T-type channels extend the dynamic range of cones and may improve contrast detection.
A voltage ramp from a holding potential of –89 mV produces two current peaks, indicating the presence of LVA and HVA calcium channels (black). The LVA peak is eliminated when cones are held at –39 mV, where LVA channels are largely inactivated. See Davison, Lux, et al. for details.
A Region of Chromosome 21 That Reduces Aβ Plaque Burden
Paige Mumford, Justin Tosh, Silvia Anderle, Eleni Gkanatsiou Wikberg, Gloria Lau, et al.
(see pages 6453–6468)
People with Down syndrome have three copies of human chromosome 21 (Hsa21). One of the genes on this chromosome encodes amyloid precursor protein (APP), the source of β-amyloid (Aβ) peptides that accumulate in Alzheimer's disease (AD) plaques. The extra copy of APP explains why people with Down syndrome develop Aβ plaques and often develop dementia. But the onset of dementia occurs slightly later in people with Down syndrome than in people who have an extra copy of APP without full trisomy of Hsa21. Therefore, some genes on Hsa21 may slow the progress of AD.
Hsa21 contains ∼225 genes. To narrow in on genes that may influence Aβ accumulation, Mumford, Tosh, et al. generated mice possessing various portions of Hsa21 along with mouse APP harboring AD-linked mutations. Wild-type mice and mice expressing most of Hsa21 (excluding functional APP and some other genes) developed few amyloid plaques. Although mice expressing mutant APP developed numerous plaques, plaque burden was significantly reduced if a portion of Hsa21 containing just 38 genes was also present. This fragment of Hsa211 did not affect levels of soluble Aβ, suggesting that Hsa21 genes that reduce plaque load do so by promoting clearance.
The 38 genes present on the protective portion of Hsa21 included two genes previously linked to APP processing. One of these, encoding the kinase DYRK1A, phosphorylates APP and increases levels of APP and Aβ. Although DYRK1A levels were increased in mice expressing the 38-gene portion of Hsa21, APP and Aβ levels were unaltered, suggesting that the extra copy of DYRK1A did not influence amyloid pathology. Another gene present on the protective region of chromosome Hsa21 was Bace2, a secretase that cleaves APP. But the extra copy of Bace2 did not increase levels of BACE2 protein, and in individual mice, BACE2 levels were not correlated with Aβ levels.
These results support the hypothesis that genes on Hsa21 reduce accumulation or promote clearance of Aβ and narrow the list of candidate genes to ∼36. Future work should further home in on genes that influence Aβ plaque load to identify potential targets for slowing the development of AD in people with extra copies of APP.
Footnotes
This Week in The Journal was written by Teresa Esch, Ph.D.