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 GABAB receptor (GABABR), 5HT1A receptor (5HT1AR), and A1 adenosine receptor (A1R) in hippocampal neurons. Our data show that RGS6 and RGS7 make non-redundant contributions to GABABR- and 5HT1AR-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 Gαo engagement and effector access, shape GPCR-GIRK signaling dynamics in hippocampal neurons.
Keywords: G protein; G protein-coupled receptor; GIRK channel; Hippocampal neuron; Kir3; Regulator of G protein signaling.
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