Role of Ca2+ mobilizing second messenger NAADP in local and global Ca2+ signalling in mouse cardiac myocytes

Ca2+信号是心肌细胞内传递兴奋-收缩耦合的中枢信号通路。心脏ryanodine受体在这一过程中起着关键作用。内源性腺嘌呤核苷酸环adp核糖（cADPR）和烟酸腺嘌呤二核苷酸磷酸（NAADP）作为ryanodine受体的第二信使和/或调节剂，而另一种内源性腺嘌呤核苷酸腺苷二磷酸（ADPR）激活瞬时受体电位M2 （TRPM2）阳离子通道。虽然这些核苷酸在某些细胞类型中的作用是明确的，但它们在心脏中的确切作用在很大程度上仍然未知。因此，本项目的科学目标是分析(i) cADPR/Ca2+信号通路，（ii） NAADP/Ca2+信号通路，以及（iii）心肌细胞中ADPR/TRPM2/Ca2+信号通路。这些内源性腺嘌呤核苷酸的质量分析以及单细胞Ca2+成像研究，部分结合显微注射将用于实现这些目标。内源性腺嘌呤核苷酸的膜渗透类似物的发展还可能导致药物的新型先导结构。

Ca2+ signaling is the central signaling pathway in cardiac myocytes that intracellularly transmits excitation-contraction coupling. Cardiac ryanodine receptors play a pivotal role in this process. The endogenous adenine nucleotides cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) serve as second messengers and/or modulators of ryanodine receptors, while another endogenous adenine nucleotide, adenosine diphosphoribose (ADPR) activates the transient receptor potential M2 (TRPM2) cation channel. Though the role of these nucleotides is clear in some cell types, their precise role in heart remains largely unknown. Thus, the scientific goals of this project are the analysis of the (i) cADPR/Ca2+ signaling pathway, (ii) the NAADP/Ca2+ signaling pathway, and (iii) the ADPR/TRPM2/Ca2+ signaling pathway in cardiac myocytes. Mass analysis of these endogenous adenine nucleotides as well as single cell Ca2+ imaging studies, partially combined with microinjection will be used to achieve these goals. The development of membran-permeant analogues of the endogenous adenine nucleotides may in addition result in novel lead structures for pharmaceutical drugs.