Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Activates Global and Heterogeneous Local Ca2+ Signals from NAADP- and Ryanodine Receptor-gated Ca2+ Stores in Pulmonary Arterial Myocytes

Abstract

Background: NAADP activates Ca 2ϩ release from endolysosomal organelles. Results: NAADP activates two-pore channels in pulmonary arterial smooth muscle cells to elicit global and heterogeneous subcellular Ca 2ϩ signals from NAADP-and ryanodine-sensitive Ca 2ϩ stores, which contribute to the agonist-induced response. Conclusion: NAADP mediates complex Ca 2ϩ interactions between endolysosomes and the sarcoplasmic reticulum to regulate vascular reactivity and other cellular functions. Significance: The results improve our understanding of NAADP-dependent regulation of pulmonary vascular functions.

CD38 Mediates Angiotensin II–Induced Intracellular Ca2+ Release in Rat Pulmonary Arterial Smooth Muscle Cells

“…It has been suggested that a reduction of b-NAD 1 :b-NADH ratio during hypoxia stimulates cyclase activity and inhibits hydrolase activity of CD38, leading to the accumulation of cADPR to activate RyR-gated Ca 21 release for the sustained HPV (22,27). This hypothesis has yet to be verified because a recent study failed to observe the contribution of CD38 to HPV in isolated rat PAs without precontracted with a vasoactive agonist (28) (13,29). Apart from the abovementioned studies, there is no related information on any other vasoactive agonist and on the mechanism underlying agonist-induced activation of CD38 in PASMCs.…”

“…Previous studies from our and other laboratories have identified the expression of RyR and TPC subtypes and have characterized Ca 21 release signals from RyR-gated Ca 21 stores (23)(24)(25) and NAADP-gated acidic endo-lysosomes in rat PASMCs (13,21). Hence, all the components of the CD38-dependent Ca 21 pathways are operational in PASMCs.…”

“…CD38 expression has been reported in some systemic arteries, including aorta and the coronary and renal arteries (8)(9)(10). Endogenous vasoconstrictors, such as norepinephrine, endothelin-1 (ET-1), and angiotensin II (Ang II), have been shown to activate the cyclase and catalase activities of CD38, contributing to the elevation of [Ca 21 ] i and vasoconstriction (11)(12)(13)(14)(15)(16). In general, these vasoconstrictory agonists of G-protein-coupled receptors activate phospholipase C (PLC) to synthesize inositol trisphosphate (IP 3 ) and diacyglycerol from phosphatidylinositol bisphosphate.…”

“…CD38 protein in PAs and PASMCs were determined following a standard protocol (13). Primary antibodies of CD38 (1:500 dilution) (SC-7049; Santa Cruz) and actin (1:5,000 dilution) (SC-1615; Santa Cruz) and horseradish peroxidase-coupled secondary antibody (1:5,000 dilution) (SC-2020; Santa Cruz) were used.…”

“…PASMCs were isolated from intralobar PAs (300-800 mm) of male Wistar rats (150-200 g) and transiently cultured (18-20 h) as described (13).…”