Purinergic P2Y1 receptors take centre stage in autocrine stimulation of human beta cells

Abstract

Insulin secretory vesicles contain high concentrations of adenine nucleotides, which are co-released with insulin during exocytosis. There is strong evidence that ATP and ADP serve as autocrine messengers in pancreatic beta cells, but the functional effects and detailed mechanisms of action are under debate. In this issue of Diabetologia, Khan and colleagues (DOI: 10.1007/s00125-014-3368-8) present the results of their study of autocrine purinergic signalling in isolated human beta cells. Using a combination of electrophysiological techniques, Ca2++ imaging and measurements of insulin secretion, it is demonstrated that voltage-dependent Ca2++ influx triggers release of ATP/ADP, which activates purinergic receptors of the Gq/11-coupled P2Y1 isoform. Activation of these receptors leads to membrane depolarisation and phospholipase C-mediated mobilisation of Ca2+ from endoplasmic reticulum stores, which amplifies the exocytosis-triggering Ca2++ signal. In contrast, there is little evidence for involvement of ionotropic P2X receptors in the autocrine stimulation of human beta cells. This commentary discusses these findings as well as various functional and therapeutic implications of the complex purinergic signalling network in the pancreatic islet.