Insulin downregulates the expression of the Ca2+-activated nonselective cation channel TRPM5 in pancreatic islets from leptin-deficient mouse models.

We recently proposed that the transient receptor potential melastatin 5 (TRPM5) cation channel contributes to glucose-induced electrical activity of the ß cell and positively influences glucose-induced insulin release and glucose homeostasis. In this study, we investigated Trpm5 expression and function in pancreatic islets from mouse models of type II diabetes. Gene expression analysis revealed a strong reduction of Trpm5 mRNA levels in pancreatic islets of db/db and ob/ob mice. The glucose-induced Ca(2+) oscillation pattern in db/db and ob/ob islets mimicked those of Trpm5 (-/-) islets. Leptin treatment of ob/ob mice not only reversed the diabetic phenotype seen in these mice but also upregulated Trpm5 expression. Leptin treatment had no additional effect on Trpm5 expression levels when plasma insulin levels were comparable to those of the vehicle-injected control group. In murine ß cell line, MIN6, insulin downregulated TRPM5 expression in a dose-dependent manner, unlike glucose or leptin. In conclusion, our data show that increased plasma insulin levels downregulate TRPM5 expression in pancreatic islets from leptin-deficient mouse models of type 2 diabetes.

Transient receptor potential (TRP) cation channels in diabetes.

Transient Receptor Potential (TRP) proteins constitute a family of cation channels with very diverse permeation and gating properties. Likewise they have a very diverse role in mammalian physiology ranging from sensory nerve endings, the cardiac muscle to immune cells. Increasing evidence has implicated TRP channels in the pathology of diabetes, both on the level of insulin release from the pancreatic ß cells and in secondary conditions such as diabetic neuropathy, nephropathy and vasculopathy. In this review we summarize these recent findings, which all together indicate that TRP channels are interesting drug targets for the treatment of patients suffering from diabetes.

Transient receptor potential cation channels in pancreatic ß cells.

There is now overwhelming evidence that TRP channels might play a significant role in the regulation of insulin release from pancreatic ß cells, which is until now insufficiently recognized. TRP channels are abundantly expressed on ß cells. The focus of this review will be on cation channels from the melastatin TRP -subfamily. We will discuss how TRPM channels can influence Ca(2+) signaling in ß cells. Knock out models of TRPM2 and TRPM5, which show a pre-diabetic phenotype, will be illustrative for this purpose. Based on these insights, TRPM5 will be critically evaluated as a potential drug target for diabetes type II therapy, which has received currently a high interest of the pharmaceutical industry. In addition, an unexpected role of the TRP channel TRPM3 as a gatekeeper of zinc, which is required for insulin storage, will be considered. Finally, we will critically discuss the use of mouse models for the unraveling of basic mechanisms of insulin release. The study of the role of TRP channels in the regulation of insulin release is of wide interest for fundamental research, evaluation of molecular mechanisms of disease and exploration of novel drug targets for metabolic diseases.

The role of transient receptor potential cation channels in Ca2+ signaling.

The 28 mammalian members of the super-family of transient receptor potential (TRP) channels are cation channels, mostly permeable to both monovalent and divalent cations, and can be subdivided into six main subfamilies: the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and the TRPA (ankyrin) groups. TRP channels are widely expressed in a large number of different tissues and cell types, and their biological roles appear to be equally diverse. In general, considered as polymodal cell sensors, they play a much more diverse role than anticipated. Functionally, TRP channels, when activated, cause cell depolarization, which may trigger a plethora of voltage-dependent ion channels. Upon stimulation, Ca2+ permeable TRP channels generate changes in the intracellular Ca2+ concentration, [Ca2+]i, by Ca2+ entry via the plasma membrane. However, more and more evidence is arising that TRP channels are also located in intracellular organelles and serve as intracellular Ca2+ release channels. This review focuses on three major tasks of TRP channels: (1) the function of TRP channels as Ca2+ entry channels; (2) the electrogenic actions of TRPs; and (3) TRPs as Ca2+ release channels in intracellular organelles.

Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5-/- mice.

Glucose homeostasis is critically dependent on insulin release from pancreatic beta-cells, which is strictly regulated by glucose-induced oscillations in membrane potential (V(m)) and the cytosolic calcium level ([Ca(2+)](cyt)). We propose that TRPM5, a Ca(2+)-activated monovalent cation channel, is a positive regulator of glucose-induced insulin release. Immunofluorescence revealed expression of TRPM5 in pancreatic islets. A Ca(2+)-activated nonselective cation current with TRPM5-like properties is significantly reduced in Trpm5(-/-) cells. Ca(2+)-imaging and electrophysiological analysis show that glucose-induced oscillations of V(m) and [Ca(2+)](cyt) have on average a reduced frequency in Trpm5(-/-) islets, specifically due to a lack of fast oscillations. As a consequence, glucose-induced insulin release from Trpm5(-/-) pancreatic islets is significantly reduced, resulting in an impaired glucose tolerance in Trpm5(-/-) mice.