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.