Leptin modulates pancreatic β-cell membrane potential through Src kinase-mediated phosphorylation of NMDA receptors
| Autor: | Jeremy Dunford, Assmaa ElSheikh, Yi Wu, Zhongying Yang, Show Ling Shyng, Dale A. Fortin, Paul Kievit, Veronica A. Cochrane |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Leptin Biochemistry Receptors N-Methyl-D-Aspartate Cell Line Diabetes Mellitus Experimental Membrane Potentials 03 medical and health sciences Mice Insulin-Secreting Cells Animals Humans Obesity Phosphorylation Molecular Biology Leptin receptor 030102 biochemistry & molecular biology Kinase Chemistry digestive oral and skin physiology Cell Biology Membrane hyperpolarization Mice Mutant Strains Cell biology 030104 developmental biology src-Family Kinases nervous system Diabetes Mellitus Type 2 Mutation NMDA receptor Signal transduction hormones hormone substitutes and hormone antagonists Proto-oncogene tyrosine-protein kinase Src Signal Transduction |
| Zdroj: | J Biol Chem |
| ISSN: | 1083-351X |
| Popis: | The adipocyte-derived hormone leptin increases trafficking of K(ATP) and Kv2.1 channels to the pancreatic β-cell surface, resulting in membrane hyperpolarization and suppression of insulin secretion. We have previously shown that this effect of leptin is mediated by the NMDA subtype of glutamate receptors (NMDARs). It does so by potentiating NMDAR activity, thus enhancing Ca(2+) influx and the ensuing downstream signaling events that drive channel trafficking to the cell surface. However, the molecular mechanism by which leptin potentiates NMDARs in β-cells remains unknown. Here, we report that leptin augments NMDAR function via Src kinase–mediated phosphorylation of the GluN2A subunit. Leptin-induced membrane hyperpolarization diminished upon pharmacological inhibition of GluN2A but not GluN2B, indicating involvement of GluN2A-containing NMDARs. GluN2A harbors tyrosine residues that, when phosphorylated by Src family kinases, potentiate NMDAR activity. We found that leptin increases phosphorylation of Tyr-418 in Src, an indicator of kinase activation. Pharmacological inhibition of Src or overexpression of a kinase-dead Src mutant prevented the effect of leptin, whereas a Src kinase activator peptide mimicked it. Using mutant GluN2A overexpression, we show that Tyr-1292 and Tyr-1387 but not Tyr-1325 are responsible for the effect of leptin. Importantly, β-cells from db/db mice, a type 2 diabetes mouse model lacking functional leptin receptors, or from obese diabetic human donors failed to respond to leptin but hyperpolarized in response to NMDA. Our study reveals a signaling pathway wherein leptin modulates NMDARs via Src to regulate β-cell excitability and suggests NMDARs as a potential target to overcome leptin resistance. |
| Databáze: | OpenAIRE |
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