Gi/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. G i/o protein-coupled receptors (G i/o -GPCRs) limit β-cell insulin secretion by decreasing Ca 2+ entry; however, the underlying mechanism has not been identified. Here, the authors show that G i/o -GPCRs hyperpolarize mouse and human β-cell membrane potential by activating Na + /K + ATPases.