TRPC3 Regulates Islet Beta‐Cell Insulin Secretion

Abstract

Insulin release is tightly controlled by glucose-stimulated calcium (GSCa) through hitherto equivocal pathways. This study investigates TRPC3, a non-selective cation channel, as a critical regulator of insulin secretion and glucose control. TRPC3's involvement in glucose-stimulated insulin secretion (GSIS) is studied in human and animal islets. TRPC3-dependent in vivo insulin secretion is investigated using pharmacological tools and Trpc3 −/− mice. TRPC3's involvement in islet glucose uptake and GSCa is explored using fluorescent glucose analogue 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose and calcium imaging. TRPC3 modulation by a small-molecule activator, GSK1702934A, is evaluated in type 2 diabetic mice. TRPC3 is functionally expressed in human and mouse islet beta cells. TRPC3-controlled insulin secretion is K ATP -independent and primarily mediated by diacylglycerol channel regulation of the cytosolic calcium oscillations following glucose stimulation. Conversely, glucose uptake in islets is independent of TRPC3. TRPC3 pharmacologic inhibition and knockout in mice lead to defective insulin secretion and glucose intolerance. Subsequently, TRPC3 activation through targeted small-molecule enhances insulin secretion and alleviates diabetes hallmarks in animals. This study imputes a function for TRPC3 at the onset of GSIS. These insights strengthen one's knowledge of insulin secretion physiology and set forth the TRPC3 channel as an appealing candidate for drug development in the treatment of diabetes.

PACS-1 Interacts with TRPC3 and ESyt1 to Mediate Protein Trafficking while Promoting SOCE and Cooperatively Regulating Hormone Secretion

“…As these PACS-1 null conditions increased PM-localized ESyt-1, we hypothesize that ESyt-1 fails to localize to DAG PM microdomains, where ESyt-1 would regulate ACTH secretion via lipid exchanges . Interestingly, TRPC3 knockout was recently demonstrated to regulate insulin secretion in murine islet β-cells . Therefore, further elucidating the specific mechanisms PACS-1 uses to regulate the regulated secretory pathways with ESyt-1, and potentially TRPC3, are future avenues for investigation.…”

“…38 Interestingly, TRPC3 knockout was recently demonstrated to regulate insulin secretion in murine islet β-cells. 50 Therefore, further elucidating the specific mechanisms PACS-1 uses to regulate the regulated secretory pathways with ESyt-1, and potentially TRPC3, are future avenues for investigation.…”

Role of TRP Channels in Metabolism-Related Diseases

“…TRPC1 can contribute to insulin secretion in rat pancreatic β cells by mediating the functionality of store-operated Ca 2+ (SOC) channels [174]. TRPC3, functionally expressed in human and mouse pancreatic islet cells, can lead to defective insulin secretion and impaired glucose tolerance in pancreatic β cells if pharmacologically inhibited or removed [175]. TRPC4 is suggested to be involved in M2 and M3 muscarinic receptor signaling, implying its potential role in acetylcholine-induced insulin action in native pancreatic β cells [176].…”