Gi/o protein–coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na+/K+ ATPase activation
ABSTRACT Gi/o protein-coupled receptors (Gi/o-GPCRs) limit pancreatic islet insulin secretion by decreasing β-cell Ca2+ entry, which is essential for maintenance of glucose homeostasis. However, the Gi/o-GPCR signaling mechanism that mediates inhibition of human islet hormone secretion has not been identified. Here we demonstrate that Gi/o-GPCRs cause hyperpolarization of the β-cell membrane potential through activation of Na+/K+ ATPases (NKAs) in mouse and human islets. Stimulation of Gi/o-coupled somatostatin or α2-adrenergic receptors induced oscillations in β-cell NKA activity, which resulted in islet Ca2+ fluctuations. Selective induction of β-cell Gi/o signaling with a chemogenetic Gi/o-GPCR also activated NKAs and initiated islet Ca2+ oscillations, suggesting that β-cell Gi/o-GPCRs tune pulsatile insulin secretion. Furthermore, intra-islet paracrine activation of β-cell Gi/o-GPCR signaling and NKAs by δ-cell somatostatin secretion slowed Ca2+ oscillations, which decreased insulin secretion. Gi/o-GPCR-mediated oscillations in β-cell membrane potential and Ca2+ were dependent on NKA phosphorylation by Src tyrosine kinases; an effect that was mimicked by stimulating islet insulin receptor tyrosine kinases. Whereas β-cell NKA function was completely inhibited by cAMP-dependent PKA activation. Taken together, these data reveal that NKA-mediated hyperpolarization of β-cell membrane potential serves as the primary and conserved mechanism for Gi/o-GPCR control of electrical excitability, Ca2+ handling, and insulin secretion..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 14. Feb. Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dickerson, Matthew T. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2022.02.10.479802 |
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| PPN (Katalog-ID): |
XBI035221771 |
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| 520 | |a ABSTRACT Gi/o protein-coupled receptors (Gi/o-GPCRs) limit pancreatic islet insulin secretion by decreasing β-cell Ca2+ entry, which is essential for maintenance of glucose homeostasis. However, the Gi/o-GPCR signaling mechanism that mediates inhibition of human islet hormone secretion has not been identified. Here we demonstrate that Gi/o-GPCRs cause hyperpolarization of the β-cell membrane potential through activation of Na+/K+ ATPases (NKAs) in mouse and human islets. Stimulation of Gi/o-coupled somatostatin or α2-adrenergic receptors induced oscillations in β-cell NKA activity, which resulted in islet Ca2+ fluctuations. Selective induction of β-cell Gi/o signaling with a chemogenetic Gi/o-GPCR also activated NKAs and initiated islet Ca2+ oscillations, suggesting that β-cell Gi/o-GPCRs tune pulsatile insulin secretion. Furthermore, intra-islet paracrine activation of β-cell Gi/o-GPCR signaling and NKAs by δ-cell somatostatin secretion slowed Ca2+ oscillations, which decreased insulin secretion. Gi/o-GPCR-mediated oscillations in β-cell membrane potential and Ca2+ were dependent on NKA phosphorylation by Src tyrosine kinases; an effect that was mimicked by stimulating islet insulin receptor tyrosine kinases. Whereas β-cell NKA function was completely inhibited by cAMP-dependent PKA activation. Taken together, these data reveal that NKA-mediated hyperpolarization of β-cell membrane potential serves as the primary and conserved mechanism for Gi/o-GPCR control of electrical excitability, Ca2+ handling, and insulin secretion. | ||
| 700 | 1 | |a Dadi, Prasanna K. |e verfasserin |4 aut | |
| 700 | 1 | |a Zaborska, Karolina E. |e verfasserin |4 aut | |
| 700 | 1 | |a Nakhe, Arya Y. |e verfasserin |4 aut | |
| 700 | 1 | |a Schaub, Charles M. |e verfasserin |4 aut | |
| 700 | 1 | |a Dobson, Jordyn R. |e verfasserin |4 aut | |
| 700 | 1 | |a Wright, Nicole M. |e verfasserin |4 aut | |
| 700 | 1 | |a Lynch, Joshua C. |e verfasserin |4 aut | |
| 700 | 1 | |a Scott, Claire F. |e verfasserin |4 aut | |
| 700 | 1 | |a Jacobson, David A. |e verfasserin |4 aut | |
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