BPS2026 - Mechanism of urea activators of GIRK1/GIRK2 versus GIRK1/GIRK4 channels

G-protein-gated inwardly-rectifying potassium channels (GIRKs) are activated by the Gbg dimers of Gi/o-protein-signaling systems to inhibit cell excitability. GIRK channels exist as homotetramers (GIRK2 and GIRK4) or heterotetramers with nonfunctional homomeric subunits (GIRK1 and GIRK3). Their activation inhibits excitability, slowing the rate of pacemaker and atrial cell firing in the heart or opposing excitation of post-synaptic neurons in the brain. Dysregulation of GIRK function has been linked to arrhythmias, epilepsy, addiction, and neuropsychiatric disorders, underscoring their biomedical relevance and the need for specific pharmacological modulators. GIRK2 and GIRK4 channels form homo- and heterotetramers with GIRK1. Several studies, performed over a decade starting in 1995, suggested a 2:2 stoichiometry of GIRK1 with either the GIRK2 or GIRK4 subunits. Structure determination of GIRK1/2 and GIRK1/4 heterotetramers with and without urea activators have revealed surprising distinct asymmetric stoichiometries for each of the two heterotetrameric channels. Electrophysiological studies and molecular dynamics simulations have underscored the importance of specific interactions made by the drugs with key residues and have shed light into key differences underlying the differential responses to urea drugs.