G _i/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 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.

Abstract

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.