At the center of the circle: purinergic signaling in the autocrine loops of pancreatic islets

Abstract

The endocrine pancreas is essential for monitoring and regulating the metabolic status of the body by sensing changes in glucose and free fatty acids and respond by secreting hormones such as insulin and glucagon. Although pancreatic islets only make up a small percentage of the pancreas mass, its malfunction causes severe disease. Despite insulin treatment, and the development of novel antidiabetic drugs, diabetes is still one of the most costly and invaliding diseases, leaving an open arena for drug target discovery within the endocrine pancreas. Purinergic receptors are a class of receptors, which has already been utilized as a successful antithrombotic drug target used in secondary prevention after myocardial infarction. The versatility and broad expression of these receptors make them interesting for pharmacological manipulation in treatment of disease. Purinergic receptors include four G-protein coupled adenosine receptors (A1, A2A, A2B, and A3), eight G-protein coupled nucleotide (ATP, ADP, UTP, UDP, UDPglucose) gated receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14), and finally seven ATP-gated ion channels (P2X1-7). Ectonucleotidases degrade nucleotides to their di-and mono derivatives, which in turn can stimulate their favored P2 receptor. Adenosine monophosphate (AMP) is finally hydrolyzed to adenosine, which in turn can act on adenosine receptors. Each P2Y receptor couples to different G-proteins leading to different intracellular pathways downstream of stimulation.

Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release

“…Since then, the mechanisms of nucleotide-mediated regulation of insulin release have been intensively studied with partially conflicting results and have recently been reviewed in detail [8,[263][264][265]. Notably, the impact of nucleotides and the cellular mechanisms leading to insulin release vary between species.…”

“…ATPinduced insulin release from pancreatic β cells is one example [264,265,279]. Similarly, ATP co-released from nerve termin a l s c a n a m p l i f y -v i a f a c i l i t a t o r y p r e s y n a p t i c autoreceptors-its own release and that of the co-released neurotransmitter.…”