Membrane Phosphoinositides Control Insulin Secretion through their Effects on KATP Channel Activity

摘要

ATP-sensitive potassium channels (KATP channels) of pancreatic β-cells play key roles in glucose-stimulated insulin secretion by linking metabolic signals to cell excitability. Membrane phosphoinositides, in particular phosphatidylinositol 4,5-bisphosphates (PIP2), stimulate KATP channels and decrease channel sensitivity to ATP inhibition; as such, they have been postulated as critical regulators of KATP channels and hence of insulin secretion in β-cells. Here, we tested this hypothesis by manipulating the interactions between KATP channels and membrane phospholipids in a β-cell line, INS-1, and assessing how the manipulations affect membrane excitability and insulin secretion. We demonstrate that disruption of channel interactions with PIP2 by overexpressing PIP2-insensitive channel subunits leads to membrane depolarization and elevated basal level insulin secretion at low glucose concentrations. By contrast, facilitation of channel interactions with PIP2 by upregulating PIP2 levels via overexpression of a lipid kinase, PI-4-phosphate 5 kinase, decreases the ATP-sensitivity of endogenous KATP channels by ∼26-fold and renders INS-1 cells hyperpolarized, unable to secrete insulin properly in the face of high glucose. Our results establish an important role of the interaction between membrane phosphoinositides and KATP channels in regulating insulin secretion.