Regulation of native GABA sub(A) receptors by PKC and protein phosphatase activity

• Published in: Psychopharmacology 2005-12, Vol.183 (2), p.241-247
• Main Authors: Kumar, Sandeep, Khisti, Rahul T, Morrow, ALeslie
• Format: Article
• Language: English
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-005-0161-x

Rationale and objective: Protein kinase C (PKC) modulation of ionotropic receptors is a common mechanism for regulation of channel function. The effects of PKC and phosphatase activation on native gamma-aminobutyric acid (GABA sub(A)) receptors in adult brain are unknown. Previous studies of recombinant GABA sub(A) receptors have provided evidence that PKC activation inhibits receptor function, whereas other studies suggest that PKC either increases or does not alter GABA sub(A) receptor function. The present study explored (a) the effects of PKC and phosphatase activity on GABA-mediated super(36)Cl super(-) uptake in cerebral cortical synaptoneurosomes and (b) the effect of PKC activity on muscimol-induced loss of righting reflex (LORR) in adult rats. Methods: GABA sub(A) receptor function in vitro was measured by muscimol-induced super(36)Cl super(-) uptake into cerebral cortical synaptoneurosomes. The in vivo effect of PKC on GABA sub(A)-mediated function was measured by intracerebroventricular (i.c.v.) injection of 4-beta-phorbol-12,13-dibutyrate (PDBu) or calphostin C followed by determination of muscimol-induced LORR. Results: Adenosine triphosphate (ATP) and PDBu produced a concentration-dependent and specific reduction in muscimol-stimulated super(36)Cl super(-) uptake that was blocked by the PKC inhibitor calphostin C. Both adenosine diphosphate and 4 alpha PDBu were ineffective. Phosphatase inhibition produced similar inhibition of muscimol responses. Furthermore, i.c.v. administration of PDBu and calphostin C produced opposing effects on both the onset and the duration of muscimol-induced LORR in rats. Conclusions: The present study provides evidence that PKC activation reduces GABA sub(A) receptor function in native receptors both in vitro and in vivo. Phosphatase inhibitors decrease muscimol-mediated Cl super(-) uptake in GABA sub(A) receptors demonstrating coordinated regulation of native receptors by PKC and phosphatases.