The emerging roles and therapeutic potential of cyclin M/CorC family of Mg2+ transporters

Abstract

Cyclin M (CNNM) and its prokaryotic ortholog CorC belong to a family of proteins that function as Mg²⁺-extruding transporters by stimulating Na⁺/Mg²⁺ exchange, and thereby control intracellular Mg²⁺ levels. The Mg²⁺-extruding function of CNNM is inhibited by the direct binding of an oncogenic protein, phosphatase of regenerating liver (PRL), and this inhibition is responsible for the PRL-driven malignant progression of cancers. Studies with mouse strains deficient for the CNNM gene family revealed the importance of CNNM4 and CNNM2 in maintaining organismal Mg²⁺ homeostasis by participating in intestinal Mg²⁺ absorption and renal reabsorption, respectively. Moreover, CNNM proteins are involved in various diseases, and gene mutations in CNNM2 and CNNM4 cause dominant familial hypomagnesemia and Jalili syndrome, respectively. Genome wide association studies have also revealed the importance of CNNM2 in multiple major diseases, such as hypertension and schizophrenia. Collectively, the molecular and biological characterizations of CNNM/CorC show that they are an intriguing therapeutic target; the current status of drug development targeting these proteins is also discussed.

Keywords: CorC; Cyclin M (CNNM); Mg(2+); Phosphatase of regenerating liver (PRL); Transporter.