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Nicotinic Acid Adenine Dinucleotide Phosphate Mediates Ca²⁺ Signals and Contraction in Arterial Smooth Muscle via a Two-Pool Mechanism

From the Department of Biomedical Sciences (F.-X.B., A.M.E.), School of Biology, University of St Andrews, Fife, and University Department of Pharmacology (A.G.), University of Oxford, UK.

Correspondence to Dr A. Mark Evans, University of St Andrews, Division of Biomedical Sciences, School of Biology, Bute Building, St Andrews KY16 9TS, UK. E-mail ame3{at}st-and.ac.uk

Previous studies of arterial smooth muscle have shown that inositol 1,4,5-trisphosphate (IP₃) and cyclic ADP-ribose mobilize Ca²⁺ from the sarcoplasmic reticulum. In contrast, little is known about Ca²⁺ mobilization by nicotinic acid adenine dinucleotide phosphate, a pyridine nucleotide derived from ß-NADP⁺. We show here that intracellular dialysis of nicotinic acid adenine dinucleotide phosphate (NAADP) induces spatially restricted "bursts" of Ca²⁺ release that initiate a global Ca²⁺ wave and contraction in pulmonary artery smooth muscle cells. Depletion of sarcoplasmic reticulum Ca²⁺ stores with thapsigargin and inhibition of ryanodine receptors with ryanodine, respectively, block the global Ca²⁺ waves by NAADP. Under these conditions, however, localized Ca²⁺ bursts are still observed. In contrast, xestospongin C, an IP₃ receptor antagonist, had no effect on Ca²⁺ signals by NAADP. We propose that NAADP mobilizes Ca²⁺ via a 2-pool mechanism, and that initial Ca²⁺ bursts are amplified by subsequent sarcoplasmic reticulum Ca²⁺ release via ryanodine receptors but not via IP₃ receptors.

Key Words: NAADP • calcium • smooth muscle • sarcoplasmic reticulum • ryanodine receptors

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