ABSTRACT.Purpose: NiCl 2 (15 lM) stimulates the electroretinogram (ERG) b-wave amplitude of vertebrate retina up to 1.5-fold through its blocking of E ⁄ R-type voltage-gated Ca 2+ channels. Assuming that such an increase is mediated by blocking the release of the inhibitory neurotransmitter c-aminobutyric acid (GABA) via ionotropic GABA receptors, we tested the effect of both GABA itself and GABA-receptor antagonists such as ())bicuculline (1.51-fold increase) and (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA; 1.46-fold increase) on the b-wave amplitude. Methods: Recording of the transretinal potentials from the isolated bovine retina. Results: GABA (100 lM) reduced the b-wave amplitude only when NiCl 2 (15 lM) was applied first. Each antagonist applied on its own stimulated the b-wave amplitude only partially: subsequent NiCl 2 superfusion caused a small but additional increase, leading to a 1.69-and a 1.88-fold total increase of the amplitude by Ni 2+ plus ())bicuculline or Ni 2+ plus TPMPA, respectively. Only the application of both antagonists in combination, before superfusing low NiCl 2 (15 lM), completely prevented subsequent stimulation by NiCl 2 with a similar 1.90-fold total increase of b-wave amplitude. Those retina segments that did not respond to NiCl 2 could not be stimulated by ())bicuculline and vice versa. Conclusion: The stimulatory effect of NiCl 2 on the ERG b-wave amplitude is mainly, but not only, mediated by a NiCl 2 -sensitive, Ca v 2.3-triggered GABA release acting through ionotropic GABA-A and GABA-C receptors.
Multiple types of voltage-activated Ca2+ channels
(T, L, N, P, Q, R type) coexist in excitable cells and
participate in synaptic differentiation, secretion,
transmitter release, and neuronal plasticity. Ca2+ ions
entering cells trigger these events through their
interaction with the ion channel itself or through Ca2+
binding to target proteins initiating signalling
cascades at cytosolic loops of the ion conducting
subunit (Cava1). These loops interact with target
proteins in a Ca2+-dependent or independent manner.
In Cav2.3-containing channels the cytosolic linker
between domains II and III confers a novel Ca2+
sensitivity to E-type Ca2+ channels including phorbol
ester sensitive signalling via protein kinase C (PKC)
in Cav2.3 transfected HEK-293 cells. To understand Ca2+ and phorbol ester mediated activation of Cav2.3
Ca2+ channels, protein interaction partners of the II-III
loop were identified. FLAG-tagged II-III - loop of human
Cav2.3 was over-expressed in HEK 293 cells, and the
molecular chaperone hsp70, which is known to
interact with PKC, was identified as a novel functional
interaction partner. Immunopurified II-III loop-protein
of neuronal and endocrine Cav2.3 splice variants
stimulate autophosphorylation of PKCa, leading to the
suggestion that hsp70 - binding to the II-III loop - may
act as an adaptor for Ca2+ dependent targeting of
PKC to E-type Ca2+ channels.
The stimulatory effect of ZnCl(2) on the ERG b-wave amplitude resembles the stimulatory effect of NiCl(2) and may be mediated rather by the NiCl(2)-sensitive, Ca(v)2.3 E-/R-type voltage-gated Ca(2+) channels than by NiCl(2)-sensitive T-type channels.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.