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Mechanisms of Time-Dependent Potentiation of Insulin Release

Involvement of Nitric Oxide Synthase

From the Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee

Address correspondence and reprint requests to David W. Piston, Department of Molecular Physiology and Biophysics, 702 Light Hall, Vanderbilt University, Nashville, TN 37232. E-mail: dave.piston{at}vanderbilt.edu

Abbreviations: DMA, dimethylamiloride; HBSS, Hanks’ balanced salt solution; KRBH, Krebs-Ringer bicarbonate HEPES buffer; nNOS, neuronal nitric oxide synthase; pH_i, intracellular pH; TDI, time-dependent inhibition; TDP, time-dependent potentiation; TPEM, two-photon excitation microscopy

Time-dependent potentiation (TDP) of insulin release is normally absent in mice. However, we recently demonstrated that TDP occurs in mouse islets under conditions of forced decrease of intracellular pH (pH_i) associated with elevated NADPH+H⁺ (NADPH) levels. Hence, TDP in mouse islets may be kept suppressed by neuronal nitric oxide (NO) synthase (nNOS), an NADPH-utilizing enzyme with alkaline pH optimum. To determine the role of nNOS in the suppression of TDP in mouse islets, glucose-induced TDP was monitored in mouse islets in which nNOS activity had been genetically removed or chemically inhibited and compared with the TDP response in wild-type mouse islets with and without forced intracellular acidification. Genetic deletion of nNOS was provided by an nNOS knockout (NOS-KO) mouse model, B6–129S4-Nos1^tm1Plh/J. To explore how nNOS inhibits TDP, we compared pH_i and NADPH levels in wild-type and NOS-KO islets and monitored TDP with various components of the nNOS reaction added. Glucose normally does not produce TDP in wild-type mouse islets except under forced intracellular acidification. Remarkably, glucose produced strong TDP in NOS-KO islets and in wild-type islets treated with nNOS inhibitors. TDP in NOS-KO islets was not inhibited by the addition of NO, and NOS-KO islets exhibited a lower pH_i than wild-type islets. The addition of arginine to wild-type islets also enabled glucose to induce TDP. Our results show that nNOS activity contributes to the absence of TDP in mouse islets putatively through depletion of intracellular arginine.

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