1.A.2.1.12
G protein-activated inward rectifying K⁺ channel 1 (Kir3.1; IRK3; KCNJ3; GIRK1). Regulates the heartbeat in humans. Phosphatidylinositol bisphosphate (PIP2) activates by opening the intracelluar G-loop gate (Meng et al., 2012).  Along the ion permeation pathway, three relatively narrow regions (the selectivity filter, the inner helix bundle crossing, and the cytosolic G loop) may serve as gates to control ion permeation (Meng et al. 2016). Cholesterol up-regulates neuronal GIRK channel activity (Bukiya et al. 2017). Changes in the levels of cholesterol and PI(4,5)P2 may act in concert to provide fine-tuning of Kir3 channel function (Bukiya et al. 2017). Kir3.1 forms oligomers with Kir3.4 (TC# 1.A.2.1.3) and transporters Rb⁺ and spermine.  It has been suggested that the selectivity filter is responsible for inward rectification and agonist activation as well as permeation and block (Makary et al. 2006). Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification (Pegan et al. 2005). A key basic residue that coordinates PIP2 to stabilize the pre-open and open states of the transmembrane gate flips in the inhibited state to form a direct salt-bridge interaction with the cytosolic gate and destabilize its open state (Gazgalis et al. 2022).