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, Ca 2+ imaging and measurements of insulin secretion, it is demonstrated that voltage-dependent Ca 2+ influx triggers release of ATP/ADP, which activates purinergic receptors of the G q/11 -coupled P2Y 1 isoform. Activation of these receptors leads to membrane depolarisation and phospholipase C-mediated mobilisation of Ca 2+ from endoplasmic reticulum stores, which amplifies the exocytosis-triggering Ca 2+ 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. . The nucleotides are co-released with insulin during vesicle exocytosis and the local concentration of ATP at the beta cell surface may then reach micromolar levels [5]. The small size of ATP and related nucleotides allows them to escape through the granule fusion pore before insulin is released, and sometimes even without concomitant protein secretion [6]. The purine nucleotides exert auto-and paracrine actions on beta cells, and although there is extensive literature on the subject (reviewed in [7,8]), the precise receptors and molecular mechanisms involved have not been clarified.Two classes of purinergic P2 receptors mediate the effects of ATP and ADP: ionotropic P2X receptors and G-proteincoupled P2Y receptors. The P2X receptors constitute a group of seven isoforms that act as ATP-gated cation channels, several of which are expressed in beta cells [7,8]. Many of the eight P2Y family members are also present in beta cells, with a dominant role of the G q/11 -coupled P2Y 1 receptor [7,9]. Extracellular ATP has been found to amplify glucosestimulated insulin secretion in both rodent and human studies [7], but inhibitory effects have also been demonstrated, at least in the mouse [10,11]. A negative effect of ATP is also supported by the observation that glucose-induced insulin secretion is enhanced in P2Y 1 -knockout mice [12] and that a P2Y 1 receptor antagonist increases insulin secretion in the perfused rat pancreas [13]. However, recent studies support a stimulatory autocrine effect in human beta cells, although

ATP is an essential autocrine factor for pancreatic β‐cell signaling and insulin secretion

“…ATP has been previously identified among para‐ and autocrine signaling factors in the extracellular space of rodent and human pancreatic islets to act on P2 purinergic receptors (Jacques‐Silva et al, 2010 ; Tengholm, 2014 ). Effects of autocrine ATP as an extracellular signaling factor were investigated on the pancreatic cell lines MIN6 (murine) (Ishihara et al, 1993 ) and 1.1B4 (human) (McCluskey et al, 2011 ) as well as on isolated mouse primary β‐cells.…”

“…Acting on G‐protein‐coupled P2Y receptors and ionotropic P2X receptors, ATP increases [Ca 2+ ] i by stimulating InsP 3 ‐mediated Ca 2+ release from the endoplasmic reticulum (ER) (Khan et al, 2014 ) or by increased Ca 2+ influx into the cell. External ATP was suggested to promote intra‐ and inter‐islet propagation of [Ca 2+ ] i oscillations in a para‐, and autocrine fashion within the enclosed pancreatic islet (Burnstock & Novak, 2013 ; Petit et al, 1998 ; Tengholm, 2014 ). Thereby, ATP entrains pancreatic islets into a common rhythm, to make islets sensitive to fluctuating glucose levels and to ensure rapid and adapted glucose responsiveness (Grapengiesser et al, 2004 , 2005 ; Hellman et al, 2004 ; Jacques‐Silva et al, 2010 ; Petit et al, 2009 ).…”

Autocrine Signaling Underlies Fast Repetitive Plasma Membrane Translocation of Conventional and Novel Protein Kinase C Isoforms in β Cells

“…The effects of adenine nucleotides on β cells are pleiotropic and involve the action of several purinergic receptors (reviewed in Refs. 48 , 49 ). Recent work in human β cells confirmed that P2Y 1 receptors mediate autocrine stimulation of insulin secretion ( 50 ).…”

ATP Secretion and Metabolism in Regulating Pancreatic Beta Cell Functions and Hepatic Glycolipid Metabolism

“…Moreover, activation of P2X3 and P2Y13 also exerted deleterious effects on insulin secretion in pancreatic β cells ( Petit et al, 2009 ). In contrast, P2Y1 can be activated by Ca 2+ -induced ATP release to depolarize cell membrane and amplify Ca 2+ signals, augmenting insulin secretion in pancreatic β cells ( Hellman et al, 2004 ; Tengholm, 2014 ).…”