A role for PKD1 in insulin secretion downstream of P2Y1 receptor activation in mouse and human islets. Issue 19 (7th October 2019)

• Record Type: Journal Article
• Authors: Khan, Shara; Ferdaoussi, Mourad; Bautista, Austin; Bergeron, Valérie; Smith, Nancy; Poitout, Vincent; MacDonald, Patrick E.
• Is Part Of: Physiological reports. Volume 7:Issue 19(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-10-07
• Subjects: ATP -- BMI -- insulin -- P2Y1 -- PKD1 -- β cells; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.14250
• Languages: English
• ISSNs: 2051-817X

Abstract

Abstract: Along with insulin, β ‐cells co‐secrete the neurotransmitter ATP which acts as a positive autocrine signal via P2Y1 receptors to activate phospholipase C and increase the production of diacylglycerol (DAG). However, the downstream signaling that couples P2Y1 activation to insulin secretion remains to be fully elucidated. Since DAG activates protein kinase D1 (PKD1) to potentiate glucose‐stimulated insulin release, we hypothesized that autocrine ATP signaling activates downstream PKD1 to regulate insulin secretion. Indeed, we find that the P2Y1 receptor agonists, MRS2365 and ATP induce, PKD1 phosphorylation at serine 916 in mouse islets. Similarly, direct depolarization of islets by KCl caused PKD1 activation, which is reduced upon P2Y1 antagonism. Potentiation of insulin secretion by P2Y1 activation was lost from PKD1 −/− mouse islets, and knockdown of PKD1 reduced the ability of P2Y1 activation to facilitate exocytosis in single mouse β ‐cells. Finally, qPCR analysis confirmed PKD1 transcript ( PRKD1 ) expression in human islets, and insulin secretion assays showed that inhibition of either P2Y1 or PKD1 signaling impaired glucose‐stimulated insulin secretion. Human islets showed donor‐to‐donor variation in their responses to both P2Y1 and PKD1 inhibition, however, and we find that the P2Y1 ‐PKD1 pathway contributes a substantially greater proportion of insulin secretion from islets of overweight and obese donors. Thus, PKD1 promotes increased insulin secretion, likely mediating an autocrine ATP effect via P2Y1 receptor activation which may be more important in islets of donors who are overweight or obese. Abstract : Insulin secretion from pancreatic islets of Langerhans is regulated by many external and internal cues. Autocrine signalling by small molecules such as ATP co‐released with insulin can control secretion in a feed‐forward manner. We show that PKD1 is important for the facilitation of insulin secretion in response to activation of purinergic receptors by ATP, and that this plays an important role in insulin secretion from islets of obese human donors.