Calmodulin Is the Fundamental Regulator of NADK-Mediated NAD Signaling in Plants

Calcium (Ca²⁺) signaling and nicotinamide adenine dinucleotide (NAD) signaling are two basic signal regulation pathways in organisms, playing crucial roles in signal transduction, energy metabolism, stress tolerance, and various developmental processes. Notably, calmodulins (CaMs) and NAD kinases (NADKs) are important hubs for connecting these two types of signaling networks, where CaMs are the unique activators of NADKs. NADK is a key enzyme for NADP (including NADP⁺ and NADPH) biosynthesis by phosphorylating NAD (including NAD⁺ and NADH) and therefore, maintains the balance between NAD pool and NADP pool through an allosteric regulation mode. In addition, the two respective derivatives from NAD⁺ (substrate of NADK) and NADP⁺ (product of NADK), cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), have been considered to be the important messengers for intracellular Ca²⁺ homeostasis which could finally influence the combination between CaM and NADK, forming a feedback regulation mechanism. In this review article, we briefly summarized the major research advances related to the feedback regulation pathway, which is activated by the interaction of CaM and NADK during plant development and signaling. The theories and fact will lay a solid foundation for further studies related to CaM and NADK and their regulatory mechanisms as well as the NADK-mediated NAD signaling behavior in plant development and response to stress.