1.A.2.1.3
G-protein activated IRK5 (Kir3.4, KCNJ5, GIRK4) channel. The p75 neurotrophin receptor mediates cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate (Coulson et al., 2008). Cholesterol up-regulates neuronal GIRK channel activity (Bukiya et al. 2017). It forms an oligomeric channel with Kir3.1, transporting K⁺, Rb⁺ and spermine.  The selectivity filter may be responsible for inward rectification and agonist activation as well as permeation and block by Cs⁺ (Makary et al. 2006). Ivermictin activates GIRK channels in a PIP₂-dependent manner (Chen et al. 2017). GIRK channels function as either homomeric (i.e., GIRK2 and GIRK4) or heteromeric (e.g., GIRK1/2, GIRK1/4, and GIRK2/3) tetramers (Cui et al. 2022). Activators, such as ML297, ivermectin, and GAT1508, activate heteromeric GIRK1/2 channels better than GIRK1/4 channels with varying degrees of selectivity but not homomeric GIRK2 and GIRK4 channels. VU0529331 was the first homomeric GIRK channel activator, but it shows weak selectivity for GIRK2 over GIRK4 homomeric channels. The first highly selective small-molecule activator targeting GIRK4 homomeric channels is 3hi2one-G4 (3-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-3-hydroxy-1-(1-naphthylmethyl)-1,3-dihydro-2H-indol-2-one). 3hi2one-G4 does not activate GIRK2, GIRK1/2, or GIRK1/4 channels. The binding site of 3hi2one-G4 is formed by TMSs 1 and 2, and slide helix regions of the GIRK4 channel, near the phosphatidylinositol-4,5-bisphosphate binding site; it causes channel activation by strengthening channel-phosphatidylinositol-4,5-bisphosphate interactions. Slide helix residue L77 in GIRK4, corresponding to residue I82 in GIRK2 is a major determinant of isoform-specific selectivity (Cui et al. 2022). Cardiovascular and metabolic characteristics of KCNJ5 somatic mutations are important for primary aldosteronism (Chang et al. 2023).