Citrulline-argininosuccinate-arginine cycle coupled to Ca2+-signaling in rat pancreatic beta-cells.
Pancreatic beta-cells possess nitric oxide (NO) synthases (NOSs) which synthesize NO and L-citrulline from L-arginine. The present study was designed to explore the mechanism of citrulline and arginine metabolism in beta-cells and its possible coupling to beta-cell functions. The enzymes involved in citrulline-arginine metabolism, argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), and NOS were expressed in rat islets and insulinoma HIT T15 cells. In the presence of stimulatory glucose, L-citrulline and L-argininosuccinate at physiological concentrations (0.1-1 mM) increased cytosolic Ca2+ concentration ([Ca2+]i) in rat beta-cells. The citrulline-induced [Ca2+]i increase was inhibited by a NOS inhibitor, N(G)-monomethyl-L-arginine (NMMA). L-citrulline also stimulated NO production in HIT cells, which was inhibited by NMMA. In conclusion, L-citrulline is metabolized by ASS-ASL-NOS cycle to produce NO, which in turn increases [Ca2+]i in beta-cells.
Nakata
M
M
Department of Laboratory Medicine, Faculty of Medicine, Kagoshima University, Japan.
Yada
T
T
Nakagawa
S
S
Kobayashi
K
K
Maruyama
I
I
D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001123:Argininosuccinate Lyase / Q000096:biosynthesis*; D001124:Argininosuccinate Synthase / Q000096:biosynthesis*; D001125:Argininosuccinic Acid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism* / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D007150:Immunohistochemistry; D007340:Insulinoma; D007515:Islets of Langerhans / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D010190:Pancreatic Neoplasms; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D019323:omega-N-Methylarginine / Q000494:pharmacology
D012333:RNA, Messenger; D001125:Argininosuccinic Acid; D019323:omega-N-Methylarginine; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D001123:Argininosuccinate Lyase; D001124:Argininosuccinate Synthase; D002118:Calcium