Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent endogenous Ca2+ mobilizing second messenger that is known to release Ca2+ from the acidic endolysosomal vesicles. Our previous work showed that intracellular application of NAADP led to the increase in contractions of ventricular cardiomyocytes, accompanied by an increase in sarcoplasmic reticulum Ca2+ load. Previously, it has been reported that beta-adrenergic activation increases NAADP level in guinea pig heart, and we therefore hypothesized that the inotropic effect of beta-adrenergic activation is partly mediated by NAADP.
Two-pore channel 2 (Tpc2) is known to mediate NAADP-regulated endolysosomal calcium release. We showed that intracellular application of NAADP on electrically stimulated ventricular myocytes increased calcium transient amplitude in wild-type but not Tpc2-KO mice. Strikingly, Tpc2-KO ventricular cardiomyocytes also showed a reduced isoprenaline-induced increase in contraction and calcium transient amplitudes compared to wild-type mice, establishing the contribution of NAADP to the beta-adrenergic pathway-regulated inotropic effect. To dissect the downstream mechanism, we showed that Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor, KN93 preincubation abolished the NAADP-induced increase in calcium transient amplitude. This is consistent with CaMKII acting as a downstream effector of beta-adrenergic activation that amplifies SR calcium uptake.
We report here that the NAADP signaling cascade is a novel downstream pathway of beta-adrenergic activation in ventricular cardiomyocytes. This pathway requires functional Tpc2 channels and is partly if not entirely mediated through the activation of CaMKII by the NAADP-released Ca2+, which subsequently enhances SR Ca2+ uptake, contributing to the inotropic effect of cardiac beta-adrenergic activation.
- CARDIAC PROCEDURES AND THERAPY
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