title: P2Y purinergic receptor-regulated insulin secretion is mediated by a cAMP/Epac/Kv channel pathway.
abstract: Enhancement of insulin secretion is a major therapeutic approach for type 2 diabetes (T2D). Activation of P2Y purinergic receptor (P2YR) causes potentiation of insulin secretion in a glucose-dependent manner, making it a promising therapeutic target for T2D. Here we show that activation of P2YR to potentiate insulin secretion is mediated by adenylyl cyclase/cyclic AMP (cAMP) and the downstream effector, exchange protein directly activated by cAMP (Epac), leading to inhibition of voltage-dependent potassium (Kv) channels. P2YR-mediated Kv channel inhibition results in prolongation of action potential duration, and in turn elevates intracellular Ca(2+) level and insulin secretion. Taken together, the data indicate that cAMP/Epac/Kv channel pathway mediates P2YR-regulated insulin secretion, which may have important therapeutic implications for T2D.
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China. Electronic address: yizhang313@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China. Electronic address: gqluckyy@163.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China. Electronic address: 18734893498@163.com.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China. Electronic address: 13633513158@163.com.
authors.forename: Jingying
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Endocrinology, the First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China. Electronic address: nectarliu@163.com.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, the First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China. Electronic address: yangjlm@126.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Shanxi Medical University, Taiyuan, China. Electronic address: sxlqs2012@163.com.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Li
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058470:Receptors, Purinergic P2Y / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D015221:Potassium Channels; C526973:Rapgef3 protein, rat; D058470:Receptors, Purinergic P2Y; D000242:Cyclic AMP; D002118:Calcium
keywords: Cyclic AMP; Diabetes; Insulin secretion; P2Y purinergic receptor; Voltage-dependent potassium channels