NMDA receptors - regulatory function and pathophysiological significance for pancreatic beta cells

Abstract

Due to its unique features amongst ionotropic glutamate receptors, the NMDA receptor is of special interest in the physiological context but even more as a drug target. In the pathophysiology of metabolic disorders, particularly type 2 diabetes mellitus, there is evidence that NMDA receptor activation contributes to disease progression by impairing beta cell function. Consequently, channel inhibitors are suggested for treatment, but up to now there are many unanswered questions about the signaling pathways NMDA receptors are interfering with in the islets of Langerhans. In this review we give an overview about channel structure and function with special regard to the pancreatic beta cells and the regulation of insulin secretion. We sum up which signaling pathways from brain research have already been transferred to the beta cell, and what still needs to be proven. The main focus is on the relationship between an over-stimulated NMDA receptor and the production of reactive oxygen species, the amount of which is crucial for beta cell function. Finally, pilot studies using NMDA receptor blockers to protect the islet from dysfunction are reviewed and future perspectives for the use of such compounds in the context of impaired glucose homeostasis are discussed.

Keywords: GluN2; NMDA receptor; ROS; beta cell; insulin; pancreatic.