Abstract
It is known that desensitization of GABA(A) receptor (GABA(A)R)-mediated currents is paradoxically correlated with the slowdown of their deactivation, i.e., resensitization. It has been shown that an upregulation of calcineurin enhances the desensitization of GABA(A)R-mediated currents but paradoxically prolongs the decay phase of inhibitory postsynaptic currents/potentials without appreciable diminution of their amplitudes. The paradoxical correlation between desensitization and resensitization of GABA(A)R-mediated currents can be more clearly seen in response to a prolonged application of GABA to allow more desensitization, instead of brief pulse used in previous studies. Indeed, hump-like GABA(A)R currents were produced after a strong desensitization at the offset of a prolonged puff application of GABA in pyramidal cells of the barrel cortex, in which calcineurin activity was enhanced by deleting phospholipase C-related catalytically inactive proteins to enhance the desensitization/resensitization of GABA(A)R-mediated currents. Hump-like GABA(A)R currents were also evoked at the offset of propofol or barbiturate applications in hippocampal or sensory neurons, but not GABA applications. Propofol and barbiturate are useful to treat benzodiazepine/alcohol withdrawal syndrome, suggesting that regulatory mechanisms of desensitization/resensitization of GABA(A)R-mediated currents are important in understanding benzodiazepine/alcohol withdrawal syndrome. In this review, we will discuss the molecular and regulatory mechanisms underlying the desensitization and resensitization of GABA(A)R-mediated currents and their functional significances.