Distinct deactivation and desensitization kinetics of recombinant GABA(A) receptors

Abstract

The functional role of the large heterogeneity in GABA(A) receptor subunit genes and its role in setting the properties of inhibitory synapses in the CNS is poorly understood. A kinetic comparison between currents elicited by ultra-rapid application with a piezoelectric translator of 1 mM GABA to mammalian cells transfected with cDNAs encoding distinct GABA(A) receptor subunits revealed that the intrinsic deactivation and desensitization properties depend on subunit combination. In particular, receptors containing α6 with β2γ2 subunits were endowed with a significantly slower deactivation as compared to those receptors containing α1 with β2γ2 subunits. While densensitization produced by prolonged GABA applications on α1β2γ2 receptors was characterized by a rapid exponential decay followed by a slower decay and a steady state response, α6β2γ2 receptors lacked densensitization. Furthermore, GABA(A) receptors lacking the γ2 subunit were characterized by a much larger non-desensitizing component and a very rapid deactivation. Lastly, analysis of GABA-activated currents in cells cotransfected with α1 and α6 together with β2γ2 subunit revealed unique kinetic properties. Our results suggest that distinct subunit composition confers specific deactivation and desensitization properties that may profoundly affect synaptic decay kinetics and the capability to sustain high frequency synaptic inputs.