P2 purinergic signalling in the pancreatic beta-cell: control of insulin secretion and pharmacology.

Extracellular adenosine triphosphate is able to modulate pancreatic beta-cell function, acting on P2 purinergic ionotropic (P2X) and metabotropic (P2Y) receptors. Physiologically, ATP entrains beta-cells into a common rhythm by coordinating Ca(2+) oscillations; it plays a central role in insulin secretion pulsatility. ATP also triggers a positive feedback signal amplifying glucose-induced insulin release, which argues for a potential pharmacological application. ATP has consistently been shown to increase cytoplasmic free calcium concentration, notably in human tissue. Acting on P2X receptors, of which different molecular subtypes are expressed in beta-cells, it leads to a transient insulin release that may involve a closure of K(ATP) channels or a rapidly decaying inward current. Activation of G-protein-coupled P2Y receptors triggers different signalling pathways and amplifies insulin release in a glucose-dependent way. It has recently been shown that pancreatic beta-cells express different molecular subtypes of receptors, which may explain the complex interaction of P2Y ligands on high- and low-affinity binding sites. Despite the complexity of this purinergic pharmacology, consistent pre-clinical data suggest the potential of P2Y receptor agonists as drug candidates for type 2 diabetes.