, Volume 183, Issue 2, pp 241-247
Date: 12 Oct 2005

Regulation of native GABAA receptors by PKC and protein phosphatase activity

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access


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 (GABAA) receptors in adult brain are unknown. Previous studies of recombinant GABAA receptors have provided evidence that PKC activation inhibits receptor function, whereas other studies suggest that PKC either increases or does not alter GABAA receptor function. The present study explored (a) the effects of PKC and phosphatase activity on GABA-mediated 36Cl uptake in cerebral cortical synaptoneurosomes and (b) the effect of PKC activity on muscimol-induced loss of righting reflex (LORR) in adult rats.


GABAA receptor function in vitro was measured by muscimol-induced 36Cl uptake into cerebral cortical synaptoneurosomes. The in vivo effect of PKC on GABAA-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.


Adenosine triphosphate (ATP) and PDBu produced a concentration-dependent and specific reduction in muscimol-stimulated 36Cl uptake that was blocked by the PKC inhibitor calphostin C. Both adenosine diphosphate and 4αPDBu 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.


The present study provides evidence that PKC activation reduces GABAA receptor function in native receptors both in vitro and in vivo. Phosphatase inhibitors decrease muscimol-mediated Cl uptake in GABAA receptors demonstrating coordinated regulation of native receptors by PKC and phosphatases.