G i/o protein-coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na + /K + ATPase activation.

G i/o -coupled somatostatin or α2-adrenergic receptor activation stimulated β-cell NKA activity, resulting in islet Ca 2+ fluctuations. Furthermore, intra-islet paracrine activation of β-cell G i/o -GPCRs and NKAs by δ-cell somatostatin secretion slowed Ca 2+ oscillations, which decreased insulin secretion. β-cell membrane potential hyperpolarization resulting from G i/o -GPCR activation was dependent on NKA phosphorylation by Src tyrosine kinases. Whereas, β-cell NKA function was inhibited by cAMP-dependent PKA activity. These data reveal that NKA-mediated β-cell membrane potential hyperpolarization is the primary and conserved mechanism for G i/o -GPCR control of electrical excitability, Ca 2+ handling, and insulin secretion.