Enhanced desensitization followed by unusual resensitization in GABA^sub A^ receptors in phospholipase C-related catalytically inactive protein-1/2 double-knockout mice

Phospholipase C-related catalytically inactive proteins (PRIP-1/2) are previously reported to be involved in the membrane trafficking of GABA^sub A^ receptor (GABA^sub A^R) and the regulation of intracellular Ca^sup 2+^ stores. GABA^sub A^R-mediated currents can be regulated by the intracellular Ca^sup 2+^. However, in PRIP-1/2 double-knockout (PRIP-DKO) mice, it remains unclear whether the kinetic properties of GABA^sub A^Rs are modulated by the altered regulation of intracellular Ca^sup 2+^ stores. Here, we investigated whether GABA^sub A^R currents (I^sub GABA^) evoked by GABA puff in layer 3 (L3) pyramidal cells (PCs) of the barrel cortex are altered in PRIP-DKO mice. The deletion of PRIP-1/2 enhanced the desensitization of I^sub GABA^ but induced a hump-like tail current (tail-I) at the GABA puff offset. I^sub GABA^ and the hump-like tail-I were suppressed by GABA^sub A^R antagonists. The enhanced desensitization of I^sub GABA^ and the hump-like tail-I in PRIP-DKO PCs were mediated by increases in the intracellular Ca^sup 2+^ concentration and were largely abolished by a calcineurin inhibitor and ruthenium red. Calcium imaging revealed that Ca^sup 2+^-induced Ca^sup 2+^ release (CICR) and subsequent store-operated Ca^sup 2+^ entry (SOCE) are more potent in PRIP-DKO PCs than in wild-type PCs. A mathematical model revealed that a slowdown of GABA-unbinding rate and an acceleration of fast desensitization rate by enhancing its GABA concentration dependency are involved in the generation of hump-like tail-Is. These results suggest that in L3 PCs of the barrel cortex in PRIP-DKO mice, the increased calcineurin activity due to the potentiated CICR and SOCE enhances the desensitization of GABA^sub A^Rs and slows the GABA-unbinding rate, resulting in their unusual resensitization following removal of GABA.