Receptor-dependent influence of R7 RGS proteins on neuronal GIRK channel signaling dynamics

Most neurons are influenced by multiple neuromodulatory inputs that converge on common effectors. Mechanisms that route these signals are key to selective neuromodulation but are poorly understood. G protein-gated inwardly rectifying K⁺ (GIRK or Kir3) channels mediate postsynaptic inhibition evoked by G protein-coupled receptors (GPCRs) that signal via inhibitory G proteins. GIRK-dependent signaling is modulated by Regulator of G protein Signaling proteins RGS6 and RGS7, but their selectivity for distinct GPCR-GIRK signaling pathways in defined neurons is unclear. We compared how RGS6 and RGS7 impact GIRK channel regulation by the GABA_B receptor (GABA_BR), 5HT_1A receptor (5HT_1AR), and A₁ adenosine receptor (A₁R) in hippocampal neurons. Our data show that RGS6 and RGS7 make non-redundant contributions to GABA_BR- and 5HT_1AR-GIRK signaling and compartmentalization and suggest that GPCR-G protein preferences and the substrate bias of RGS proteins, as well as receptor-dependent differences in Gα_o engagement and effector access, shape GPCR-GIRK signaling dynamics in hippocampal neurons.