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. Author manuscript; available in PMC: 2018 Apr 1.
Published in final edited form as: Pharmacol Ther. 2016 Dec 7;172:116–126. doi: 10.1016/j.pharmthera.2016.12.002

Figure 2. Model depicting CD38/cADPR-mediated calcium release and functional effect in ASM.

Figure 2

Stimulation of ASM cells with Gq-coupled GPCR agonists results in the production of inositol 1,4,5 triphosphate (IP3) which in turn binds to its receptors on sarcoplasmic reticulum (SR). cADPR produced by the catalytic action of ADP-ribosyl cyclase (part of membrane bound protein CD38) acts as a calcium releasing second messenger presumably via ryanodine receptors (RyR) on the SR membrane. Extracellularly produced cADPR is believed to enter cell via membrane channel formed by connexin-43. Accessory proteins such as FKBP12.6 and calmodulin (CaM) are known to be involved in the cADPR-mediated calcium release. Recent studies have shown that cADPR sensitizes store-operated calcium entry via TRP channels on the plasma membrane to open and ADPR actually gates the channels. cADPR-mediated calcium release is involved in the regulation of global as well as local/compartmentalized (e.g. oscillations) calcium homeostasis in ASM cells. In vivo studies using CD38 null mice have confirmed the functional role of CD38/cADPR-mediated calcium release in the regulation of bronchomotor tone. Calcium sensitization via RhoA/ROCK contributes to ASM contraction. However, the role of cADPR in mediating calcium sensitization mechanism is not established (dotted lines). CD38 converts NADP into NAADP which is known to release calcium from intracellular stores such as lysosomes (shown on the right side of the figure).