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

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