Biology subjects

Dickerson, M. T.

Publications and source records attributed to Dickerson, M. T..

2 recordsLinked to original sources

bioRxiv2022

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

Gi/o protein-coupled receptors (Gi/o-GPCRs) limit pancreatic islet insulin secretion by decreasing {beta}-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 {beta}-cell membrane potential through activation of Na+/K+ ATPases (NKAs) in mouse and human islets. Stimulation of Gi/o-coupled somatostatin or 2-adrenergic receptors induced oscillations in {beta}-cell NKA activity, which resulted in islet Ca2+ fluctuations. Selective induction of {beta}-cell Gi/o signaling with a chemogenetic Gi/o-GPCR also activated NKAs and initiated islet Ca2+ oscillations, suggesting that {beta}-cell Gi/o-GPCRs tune pulsatile insulin secretion. Furthermore, intra-islet paracrine activation of {beta}-cell Gi/o-GPCR signaling and NKAs by {delta}-cell somatostatin secretion slowed Ca2+ oscillations, which decreased insulin secretion. Gi/o-GPCR-mediated oscillations in {beta}-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 {beta}-cell NKA function was completely inhibited by cAMP-dependent PKA activation. Taken together, these data reveal that NKA-mediated hyperpolarization of {beta}-cell membrane potential serves as the primary and conserved mechanism for Gi/o-GPCR control of electrical excitability, Ca2+ handling, and insulin secretion.

physiology↗

bioRxiv2020

TRPM7 is a critical regulator of pancreatic endocrine development and high-fat diet-induced β-cell proliferation.

The melastatin subfamily of the transient receptor potential channels (TRPM) are regulators of pancreatic {beta}-cell function. TRPM7 is the most abundant islet TRPM channel; however, the role of TRPM7 in {beta}-cell function has not been determined. Here, we utilized various spatiotemporal transgenic mouse models to investigate how TRPM7 knockout influences pancreatic endocrine development, proliferation, and function. Ablation of TRPM7 within pancreatic progenitors reduced pancreatic size, as well as -cell and {beta}-cell mass. This resulted in impaired glucose tolerance due to decreased serum insulin levels. However, ablation of TRPM7 following endocrine specification or in adult mice did not impact endocrine expansion or glucose tolerance. As TRPM7 regulates cell proliferation, we assessed how TRPM7 influences {beta}-cell hyperplasia under insulin resistant conditions. {beta}-cell proliferation induced by high-fat diet was significantly decreased in TRPM7 deficient {beta}-cells. The endocrine roles of TRPM7 may be influenced by cation flux through the channel, and indeed we find that TRPM7 ablation alters {beta}-cell intracellular Mg2+. Together, these findings reveal that TRPM7 controls pancreatic progenitor expansion and {beta}-cell proliferation, which is likely due to regulation of Mg2+ homeostasis. SummaryThis manuscript identifies a critical developmental role for TRPM7 channels in pancreatic progenitor cells. The manuscript also determines that TRPM7 plays a key role in {beta}-cell proliferation under insulin-resistant conditions.

developmental biology↗