CaMKII-Mediated Amplification is Essential to NAADP Signalling in Cardiac Myocytes

Abstract

NAADP is a highly potent endogenous Ca2+-mobilising second-messenger forming part of the beta-adrenergic response in cardiac myocytes12. Our previous work suggests NAADP causes Ca2+-release from acidic endolysosomal stores, leading to additional uptake by the SR12. Questions have arisen regarding whether the magnitude NAADP-mediated responses can be accounted for by acidic-store-mediated Ca2+ release through TPC channels34. This study aimed to confirm that TPC2 channels are required for NAADP responses in cardiac myocytes and investigate the possibility of amplification in the pathway.Transgenic mice were utilised to investigate the role of TPCs. Rapid application of NAADP-AM to WT murine ventricular myocytes elicited a significant increase in calcium transient amplitude (16±5%, P 0.05).NAADP photorelease in guinea pig atrial or ventricular myocytes caused a significant increase in calcium transient amplitude (of 37±8% and 38±9% respectively, both P 0.05, both measures, both cell types). Similarly, no changes in Ca2+ transients were observed during photorelease in the presence of the NAADP receptor antagonist, Ned-19 (P>0.05, both measures, both cell types).These data support the hypothesis that NAADP-induced Ca2+ release requires TPC2, and suggest CaMKII is the major effector for its actions in cardiac myocytes.1. Collins et al. (2011) Cell Calcium 50: 449.2. Macgregor et al. (2007) J Biol Chem 282: 15302.3. Pitt et al. (2010) J Biol Chem 285: 35039.4. Wang et al. (2012) Cell 151: 372.