Binding-pore interface of homomeric Cys-loop receptors governs kinetics of channel gating and desensitization

BARTOS M; CORRADI J; SINE S; CECILIA BEATRIZ BOUZAT

San Diego, CA, USA

Congreso; Society for Neuroscience Annual Meeting; 2007

Society for Neuroscience

Following the synaptic release and binding of neurotransmitter to Cys-loop receptors,the post-synaptic response is governed by the kinetics of channel opening, closing anddesensitization. We compare the kinetics of gating and desensitization for twohomomeric Cys-loop receptors: nicotinic α7 and 5-HT3A receptors. For 5-HT3Areceptors, agonist-evoked responses occur in episodes composed of several longopenings and brief closings whereas for α7, responses are composed mainly of asingle brief opening that terminates in a long-lived desensitized state. Kinetics ofmacroscopic and single-channel currents of the chimeric α7-5HT3A receptor areintermediate between those of α7 and 5-HT3A. To test if the intermediate kinetic profilearises from structural mismatching among loops at the interface between binding andpore domains, we generated two additional chimeras starting from α7-5HT3A: an all5HT3A chimera in which loops within the interface contain residues from 5-HT3A, and anall-α7 chimera in which these loops contain residues from α7. The analysis shows thatsubstitution of residues from the parent receptors into the interface of α7-5HT3Arecapitulates the fundamental activation and desensitization properties of the parenthomomeric receptors. Thus, the network of loops at the binding-pore interface isessential not only for coupling agonist binding to channel opening but also for dictatingthe kinetics of gating and desensitization.