Live-cell quantitative monitoring reveals distinct, high-affinity Gβγ regulations of GIRK2 and GIRK1/2 channels.

ABSTRACT: G_i/o protein-coupled receptors (GPCRs) inhibit cardiac and neuronal excitability via G protein-activated K⁺ channels (GIRK), assembled by combinations of GIRK1 - GIRK4 subunits. GIRKs are activated by direct binding of the Gβγ dimer of inhibitory G_i/o proteins. However, key aspects of this textbook signaling pathway remain debated. Recent studies suggested no G_i/o-GIRK precoupling and low (>250 μM) Gβγ-GIRK interaction affinity, contradicting earlier sub-μM estimates and implying low signaling efficiency. We show that Gγ prenylation, which mediates Gβγ membrane attachment required for GIRK activation, also contributes to the Gβγ-GIRK interaction, explaining the poor affinity obtained with non-prenylated Gβγ. Using quantitative protein titration a

SUBMITTER: Handklo-Jamal R 

PROVIDER: S-EPMC12632870 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature