Biniding-pore interface of homomeric cys-loop receptor governs kinetics of channel gating and desensitization

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

Hinxton, UK

Congreso; Nicotinic Receptors 2008; 2008

The Wellcome Trust

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 and desensitization. We compare the kinetics of gating and desensitization for two homomeric Cys-loop receptors: nicotinic alpha7 and 5-HT3A receptors. For 5-HT3A receptors, agonist-evoked responses occur in episodes composed of several long openings and brief closings whereas for alpha7, responses are composed mainly of a single brief opening that terminates in a long-lived desensitized state. Kinetics of macroscopic and single-channel currents of the chimeric alpha7-5HT3A receptor are intermediate between those of alpha7 and 5-HT3A. To test if the intermediate kinetic profile arises from structural mismatching among loops at the interface between binding and pore domains, we generated two additional chimeras starting from 7-5HT3A: an all-5HT3A chimera in which loops within the interface contain residues from 5-HT3A, and an all-alpha7 chimera in which these loops contain residues from alpha 7. The analysis shows that substitution of residues from the parent receptors into the interface of alpha7-5HT3A recapitulates the fundamental activation and desensitization properties of the parent homomeric receptors. Thus, the network of loops at the binding-pore interface is essential not only for coupling agonist binding to channel opening but also for dictating the kinetics of gating and desensitization.