ELECTROGENIC ARGININE TRANSPORT MEDIATES STIMULUS-SECRETION COUPLING IN MOUSE PANCREATIC BETA-CELLS

1. We have investigated the mechanism by which L-arginine stimulates m embrane depolarization, an increase of intracellular calcium ([Ca2+](i )) and insulin secretion in pancreatic beta-cells. 2. L-Arginine faile d to affect beta-cell metabolism, as monitored by NAD(P)H autofluoresc ence. 3. L-Arginine produced a dose-dependent increase in [Ca2+](i), w hich was dependent on membrane depolarization and extracellular calciu m. 4. The cationic amino acids L-ornithine, L-lysine, L-homoarginine ( which is not metabolized) and N-G-monomethyl-L-arginine (L-NMMA, a nit ric oxide synthase inhibitor) produced [Ca2+](i) responses similar to that produced by L-arginine. The neutral nitric oxide synthase inhibit ors N-G-nitro-L-arginine (L-NNA) and N-omega-monomethyl-L-arginine (L- NAME) also increased [Ca2+](i). D-Arginine was ineffective. 5. L-Argin ine did not affect whole-cell Ca2+ currents or ATP-sensitive K+ curren ts, but produced an inward current that was carried by the amino acid. 6. The reverse transcriptase-polymerase chain reaction demonstrated t he presence of messenger RNA for the murine cationic amino acid transp orters mCAT2A and mCAT2B within the beta-cell. 7. L-Arginine did not a ffect beta-cell exocytosis as assayed by changes in cell capacitance. 8. Our data suggest that L-arginine elevates [Ca2+](i) and stimulates insulin secretion as a consequence of its electrogenic transport into the beta-cell. This uptake is mediated by the mCAT2A transporter.