Abstract
BackgroundSo far, only indirect evidence exists for the pharmacoresistant R-type voltage-gated Ca2+ channel (VGCC) to be involved in transretinal signaling by triggering GABA-release onto ON-bipolar neurons. This release of inhibitory neurotransmitters was deduced from the sensitivity of the b-wave to stimulation by Ni2+, Zn2+ and Cu2+. To further confirm the interpretation of these findings, we compared the effects of Cu2+ application and chelation (using kainic acid, KA) on the neural retina from wildtype and Cav2.3-deficient mice. Furthermore, the immediately effect of KA on the ERG b-wave modulation was assessed.MethodsTransretinal signaling was recorded as an ERG from the superfused murine retina isolated from wildtype and Cav2.3-deficient mice.ResultsIn mice, the stimulating effect of 100 nM CuCl2 is absent in the retinae from Cav2.3-deficient mice, but prominent in Cav2.3-competent mice. Application of up to 3 mM tricine does not affect the murine b-wave in both genotypes, most likely because of chelating amino acids present in the murine nutrient solution. Application of 27 μM KA significantly increased the b-wave amplitude in wild type and Cav2.3 (−|-) mice. This effect can most likely be explained by the stimulation of endogenous KA-receptors described in horizontal, OFF-bipolar, amacrine or ganglion cells, which could not be fully blocked in the present study.ConclusionCu2+-dependent modulation of transretinal signaling only occurs in the murine retina from Cav2.3 competent mice, supporting the ideas derived from previous work in the bovine retina that R-type Ca2+ channels are involved in shaping transretinal responses during light perception.
Highlights
Only indirect evidence exists for the pharmacoresistant R-type voltage-gated Ca2+ channel (VGCC) to be involved in transretinal signaling by triggering Gamma amino butyric acid (GABA)-release onto ON-bipolar neurons
Trace metal chelation by tricine in the bovine and the murine retina The bovine retina was adapted to a phosphate buffered nutrient solution (“Sickel-medium”), which was aerated with pure oxygen and contained a reduced Ca2+ concentration to prevent precipitation of calciumphosphate
As described in a previous publication, stable ERGs from the murine retina can be recorded in a carbonate buffered nutrient solution (AMES-medium), comprising several amino acids
Summary
Only indirect evidence exists for the pharmacoresistant R-type voltage-gated Ca2+ channel (VGCC) to be involved in transretinal signaling by triggering GABA-release onto ON-bipolar neurons. This release of inhibitory neurotransmitters was deduced from the sensitivity of the b-wave to stimulation by Ni2+, Zn2+ and Cu2+. Copper-, iron-, and zinc-ions are essential in human biochemical function. Their concentration in vivo is under tight control, and a dyshomeostasis may cause electrical imbalance and consecutively, region-selective neurodegeneration eventually facilitating cognitive deficits. While Zn2+ was unaffected in any disease pathologies of the brain, both Cu2+ and Fe3+ showed a gradual age-associated decline in healthy non-cognitively impaired individuals. Among them are glutamate-, glycine-, GABA-A-, acetylcholine- and P2X- receptors as well as voltage-gated Na+ (Nav1.5), K+ (K2P, Kv1.3, mSlo1), and Ca2+ (Cav3.2) channels [4,5,6]
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