title: The PLC/PKC/Ras/MEK/Kv channel pathway is involved in uncarboxylated osteocalcin-regulated insulin secretion in rats.
abstract: Uncarboxylated osteocalcin, a bone matrix protein, has been proposed to regulate glucose metabolism by increasing insulin secretion, improving insulin sensitivity and stimulating β cell proliferation. Our previous study also indicated that uncarboxylated osteocalcin stimulates insulin secretion by inhibiting voltage-gated potassium (KV) channels. The goal of this study is to further investigate the underlying mechanisms for the regulation of Kv channels and insulin secretion by uncarboxylated osteocalcin. Insulin secretion and Kv channel currents were examined by radioimmunoassay and patch-clamp technique, respectively. Calcium imaging system was applied to measure intracellular Ca2+concentration ([Ca2+]i). The protein levels were detected by western blot. The results showed that uncarboxylated osteocalcin potentiated insulin secretion, inhibited Kv channels and increased [Ca2+]icompared to control. These effects were suppressed by phospholipase-C (PLC)/protein kinase C (PKC)/Ras/MAPK-ERK kinase (MEK) signaling pathway, indicating that this signaling pathway plays an important role in uncarboxylated osteocalcin-regulated insulinotropic effect. In addition, the results also showed that adenylyl cyclase (AC) did not influence the effect of uncarboxylated osteocalcin on insulin secretion and Kv channels, suggesting that AC is not involved in uncarboxylated osteocalcin-stimulated insulin secretion. These findings provide new insight into the mechanism of uncarboxylated osteocalcin-regulated 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.
authors.forename: Jingying
authors.initials: J
authors.lastname: Gao
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.
authors.forename: Tao
authors.initials: T
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan, China.
authors.forename: Lele
authors.initials: L
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan, China.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan, China.
authors.forename: Xiangqin
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan, China.
authors.forename: Yangyan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Shanxi Medical University, Taiyuan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
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 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: D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D015675:Osteocalcin / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D010738:Type C Phospholipases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D007328:Insulin; D024642:Potassium Channels, Voltage-Gated; D015675:Osteocalcin; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases; D010738:Type C Phospholipases; D018631:ras Proteins
keywords: Insulin secretion; Phospholipase-C; Uncarboxylated osteocalcin; Voltage-gated potassium channel