title: Inhibition of voltage-gated potassium channels mediates uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic β cells.
abstract: Insulin secretion from pancreatic β cells is important to maintain glucose homeostasis and is regulated by electrical activities. Uncarboxylated osteocalcin, a bone-derived protein, has been reported to regulate glucose metabolism by increasing insulin secretion, stimulating β cell proliferation and improving insulin sensitivity. But the underlying mechanisms of uncarboxylated osteocalcin-modulated insulin secretion remain unclear. In the present study, we investigated the relationship of uncarboxylated osteocalcin-regulated insulin secretion and voltage-gated potassium (KV) channels, voltage-gated calcium channels in rat β cells. Insulin secretion was measured by radioimmunoassay. Channel currents and membrane action potentials were recorded using the conventional whole-cell patch-clamp technique. Calcium imaging system was used to analyze intracellular Ca(2+) concentration ([Ca(2+)]i). The data show that under 16.7mmol/l glucose conditions uncarboxylated osteocalcin alone increased insulin secretion and [Ca(2+)]i, but with no such effects on insulin secretion and [Ca(2+)]i in the presence of a KV channel blocker, tetraethylammonium chloride. In the patch-clamp experiments, uncarboxylated osteocalcin lengthened action potential duration and significantly inhibited KV currents, but had no influence on the characteristics of voltage-gated calcium channels. These results indicate that KV channels are involved in uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic β cells. By inhibiting KV channels, uncarboxylated osteocalcin prolongs action potential duration, increases intracellular Ca(2+) concentration and finally promotes insulin secretion. This finding provides new insight into the mechanisms of osteocalcin-modulated insulin secretion.
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China; Department of Pediatrics, Shanxi Medical University, Taiyuan, China. Electronic address: 13633513158@163.com.
authors.forename: Jingying
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan, China. Electronic address: 1246131750@qq.com.
authors.forename: Xiangqin
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan, China. Electronic address: wding041225@163.com.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China; Department of Endocrinology, the First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China. Electronic address: baitaoy@163.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan, China. Electronic address: 1074684265@qq.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neurology, General Hospital of Lu'an Group, Changzhi, China. Electronic address: whb196910@163.com.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Wu
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: Department of Pharmacology, Shanxi Medical University, Taiyuan, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China. Electronic address: yizhang313@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D015675:Osteocalcin / Q000737:chemistry / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015220:Calcium Channels; D007328:Insulin; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D015675:Osteocalcin; D005947:Glucose; D002118:Calcium
keywords: CaCl(2)·2H(2)O (PubChem CID: 6093260); CsCl (PubChem CID: 24293); EGTA (PubChem CID: 6207); Fluo 4AM (PubChem CID: 4060965); HEPES (PubChem CID: 23831); Insulin secretion; KCl (PubChem CID: 4873); KH(2)PO(4) (PubChem CID: 516951); NaCl (PubChem CID: 5234); Poly-d-lysine hydrobromide (PubChem CID: 16219815); Tetraethylammonium chloride (PubChem CID: 5946); Uncarboxylated osteocalcin; Voltage-gated potassium channel; β cell