Redox Bridling of GIRK Channel Activity.

Abstract

pr otein-gated inw ardl y r ectifying potassium (GIRK, Kir3.x) hannels belong to the large family of inw ardl y r ectifying potasium (Kir) channels expressed throughout the body. Activation nd consequent opening of GIRK channels allow inward flow of otassium (K + ) ions into the cell resulting in membrane potenial hyperpolarization and decr eased excita bility. Thus, GIRK hannels play a key role in regulating the activity of neurons and ontrolling important physiological processes including neuonal excita bility, heart r ate , and pain per ception. 1 GIRK channels are integral membrane proteins, existing s homoor heterotetr amers. Eac h monomer features two embrane-spanning helices (M1 and M2), a re-entrant P-loop or controlling ion permeation and selectivity, and extensive ntracellular aminoand carboxy-termini crucial for channel ating. Permeation is regulated by an inner helix gate formed y the M2 segments and a cytoplasmic G-loop gate. 1 Acti v ation of GIRK channels is mediated by the direct interction of G βγ subunits, released from various G protein-coupled ece ptors (GPCRs) upon the acti v ation of inhibitory neuroransmitter r ece ptors. Howev er, the acti vity of GIRK channels epends on the presence of the membrane anionic phospholipid hosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 or PIP 2 ) while it s also modulated by ubiquitously present sodium (Na + ) ions. urthermore , GIRK c hannels ar e too r e gulated by c holesterol, hosphorylation, ethanol, etcetera. 1 The crystal structures of ecombinant GIRK channels have offered valuable insights into ow they are functionally regulated by various ligands. Thus, hannel opening is facilitated by PIP 2 at the plasma membrane, hereas G βγ and Na + modulate the c hannel’s inter action with IP 2 through conformational changes that govern the gating proess. 2 The intracellular milieu is a reducing environment charcterized by a balanced redox state. This state is crucial to upport cellular processes while serving as a pr otecti v e shield