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

Abstract

G_i/o-coupled somatostatin or α2-adrenergic receptor activation stimulated β-cell NKA activity, resulting in islet Ca²⁺ fluctuations. Furthermore, intra-islet paracrine activation of β-cell G_i/o-GPCRs and NKAs by δ-cell somatostatin secretion slowed Ca²⁺ 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, Ca²⁺ handling, and insulin secretion.