Gating of G protein Coupled Potassium Channels

Orateur : Eitan REUVENY (Weizmann Institute of Science, Rehovot, Israel)

G protein coupled potassium (GIRK/Kir3.x) channel is expressed mainly in heart and in the central nervous system (CNS). In the heart GIRK is important in the slowing down of heart rate mediated by acetylcholine, while in the CNS its main roll is in post-synaptic hyperpolarization and in maintenance of resting potential. GIRK is gated following activation of different G protein coupled receptors (GPCRs) by their ligands. Although many GPCR ligands that activate GIRK continuously stimulate the receptor, their induced GIRK currents decline immediately in the process of desensitization. Desensitization allows cells to adapt to long-term stimulation, enabling the sharp cellular response to agonist in a time-delimited manner. In this study we were looking for the mechanisms responsible for GIRK short-term desensitization. I will review the current knowledge in the field and propose a novel mechanism for GIRK desensitization where by receptor activation immediately recruits GPCR-kinases (GRKs) to compete with the channel on the G protein Gbg subunits required for channel activation. High-affinity interactions between Gbg and the GRK2 pleckstrin-homology (PH) domain result in Gbg depletion from the channel, which leads to its desensitization. Different fluorescence microscopy techniques were used to assess the simultaneity of channel desensitization with GRK2 membrane recruitments and Gbg interactions. This new phosphorylation-independent function of GRK2 forms a fast negative-feedback mechanism to enable time delimited GIRK activation, which allows for its integration in fast signaling systems such as the heart pacemaker and the nervous system.

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