Mechanism of Mutation in G Protein-Gated Inwardly Rectifying K+ Channel in Familial Hyperaldosteronism-Type III: Residue Fluctuations and Conformational Instability

Primary aldosteronism (PA) is the most common cause of secondary hypertension and accounts for 5–15% of hypertensive patients. Familial hyperaldosteronism, a monogenic cause of PA, accounts for ~1–5% of cases. Familial hyperaldosteronism type III results from mutations in the KCNJ5 gene, which lead to excessive aldosterone production and hypertension due to dysfunction of the GIRK4 channel in the adrenal gland. Despite the importance of KCNJ5 in PA pathogenesis, little is known about the molecular mechanisms underlying germline KCNJ5 mutations and their functional consequences. This study explored the structural changes in KCNJ5 pathogenic variant c.452G>A (p.Gly151Glu or GIRK4G151E). Homology modeling and molecular dynamics simulations of the mutant GIRK4 channel showed that structural rearrangements occur in GIRK4G151E when compared to GIRK4WT, displaying higher RMSD and SASA, which may be attributed to differences in residue fluctuations in the cytosolic and extracellular domains, and ligands may bind with a stronger affinity to GIRK4G151E. Given that the mutation is located within or proximal to the selectivity filter of GIRK4, we expect that the primary mechanism of dysfunction involves altered ion selectivity, leading to membrane depolarization. Our novel findings highlight the importance of understanding the molecular mechanisms underlying KCNJ5 mutations in PA and hypertension pathogenesis. This knowledge could inform the development of more targeted and effective treatments for this condition.