CAMK2G in subcellular Ca²⁺ homeostasis: Molecular mechanisms and therapeutic targeting

The Ca²⁺/calmodulin-dependent protein kinase II (CAMK2) family, consisting of subtypes A, B, D, and G, plays a pivotal role in decoding Ca²⁺ signals, an essential process in cellular communication and function. Among these, CAMK2G is notably widespread across various body tissues, with predominant expression in neurons and cardiomyocytes, where it significantly influences Ca²⁺ signal transduction and the cellular response to stress. Ca²⁺ serves as the most plentiful second messenger within the human body, orchestrating critical regulatory roles across numerous physiological and pathological contexts. It is instrumental in managing aspects of the tumor microenvironment, neurodegenerative conditions, cardiovascular diseases, and metabolic disorders. Maintaining Ca²⁺ homeostasis is crucial for the proper functioning of different subcellular organelles, impacting overall cellular health and activity. Here, we describe the central connection between CAMK2G and subcellular Ca²⁺ homeostasis, highlight the molecular functions of CAMK2G therein, and finally detail the cutting-edge therapeutic strategies targeting CAMK2G.