Internal calcium modulates apparent affinity of metabotropic GABA receptors.
The metabotropic GABA receptor (GABA(B)R) regulates calcium influx in neurons. Whole cell voltage-clamp techniques were employed to determine the effects of internal calcium on the activity of GABA(B)Rs. GABA(B)R receptor apparent affinity was maximal when bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) maintained internal calcium below 70 nM. Apparent affinity was reduced as internal calcium increased. EGTA did not produce similar effects, suggesting that localized increases in calcium influenced GABA(B)R apparent affinity. Confocal imaging disclosed relatively high internal calcium just below the plasma membrane of isolated neurons. BAPTA, but not EGTA, reduced this ring of high calcium. Heparin, dantrolene, and ryanodine increased GABA(B)R apparent affinity, effects similar to that of BAPTA. Calmodulin inhibitors also increased receptor apparent affinity. These results suggest that internally released calcium activates calmodulin, which reduces GABA(B)R apparent affinity. This identifies a reciprocal system in which the metabotropic GABA receptor can reduce calcium influx, but internal calcium can suppress this receptor pathway. Metabotropic glutamate receptors linked to inositol 1,4,5 trisphosphate (InsP(3)) raised internal calcium and suppressed the action of GABA(B)Rs. Thus negative feedback systems control the balance between excitatory and inhibitory metabotropic receptor pathways in retinal neurons.
Shen
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Departments of Physiology and Biophysics and Ophthalmology, School of Medicine, State University of New York, Buffalo, New York 14214, USA.
Slaughter
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MM
D000557:Ambystoma; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D004594:Electrophysiology; D005246:Feedback / Q000502:physiology; D005456:Fluorescent Dyes; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000037:antagonists & inhibitors; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology
D002614:Chelating Agents; D005456:Fluorescent Dyes; D018756:GABA Antagonists; D018094:Receptors, Metabotropic Glutamate; D004533:Egtazic Acid; D015544:Inositol 1,4,5-Trisphosphate; D001418:Baclofen; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid