The PACT Network: PRL, ARL, CNNM, and TRPM Proteins in Magnesium Transport and Disease

Magnesium, the most abundant divalent metal within the cell, is essential for physiological function and critical in cellular signaling. To maintain cellular homeostasis, intracellular magnesium levels are tightly regulated, as dysregulation is linked to numerous diseases, including cancer, diabetes, cardiovascular disorders, and neurological conditions. Over the past two decades, extensive research on magnesium-regulating proteins has provided valuable insight into their pathogenic and therapeutic potential. This review explores an emerging mechanism of magnesium homeostasis involving proteins in the PRL (phosphatase of regenerating liver), ARL (ADP ribosylation factor-like GTPase family), CNNM (cyclin and cystathionine β-synthase domain magnesium transport mediator), and TRPM (transient receptor potential melastatin) families, collectively termed herein as the PACT network. While each PACT protein has been studied within its individual signaling and disease contexts, their interactions suggest a broader regulatory network with therapeutic potential. This review consolidates the current knowledge on the PACT proteins' structure, function, and interactions and identifies research gaps to encourage future investigation. As the field of magnesium homeostasis continues to advance, understanding PACT protein interactions offers new opportunities for basic research and therapeutic development targeting magnesium-related disorders.