91丝瓜视频

Dr. Edgar C. Young

Associate Professor
Department of Molecular Biology and Biochemistry
Simon Fraser University, Burnaby BC

听

鈥淚ntegration of cAMP-sensing and voltage-sensing in HCN "pacemaker" channels鈥�

听

Many proteins have combined separate domains or modules during evolution to create new functions. Hyperpolarization-activated Cation (HCN) channels represent an especially complex combination of modules 鈥� a cAMP-binding fold and a voltage-sensing transmembrane domain 鈥� enabling cAMP-dependent modulation of automatic electrical rhythms in the brain and heart. It is well-established that the cAMP-sensing domain of the HCN channel is an autoinhibitory element that hinders channel opening when cAMP is absent, and that cAMP binding then relieves this autoinhibition. However, I will present our recent evidence that autoinhibition-relief is insufficient to explain all the effects of cAMP binding on HCN channels. In particular, the cAMP-sensing domain enables formation of a kinetic trap for activated (open) HCN channels, hindering the process of channel deactivation (closing). We find that whereas deletion of the cAMP-sensing domain mimics autoinhibition-relief, it disables open-state kinetic trapping. The strength of open-state trapping does not correlate with autoinhibition-relief, and therefore trapping relies on a distinct additional cAMP-dependent mechanism. Moreover, trapping efficacy is controled cooperatively by the cAMP-sensing and voltage-sensing domain, demonstrating a remarkable degree of functional integration for these disparate modules.

MANDATORY FOR GRADUATE STUDENTS