Cyclin M2 (CNNM2)

Cyclin M2 (CNNM2) is a member of the CNNM family of integral membrane proteins featuring an extracellular N-terminus, multiple transmembrane domains (DUF21), and cytosolic CBS and CNBH domains. CNNM2 is predominantly expressed in the distal convoluted tubule of the kidney and also in the brain. Functionally, it mediates Mg^2+ efflux across cell membranes and binds ATP via its CBS domains, possibly functioning as a Mg^2+ sensor rather than a direct Mg^2+ transporter. Mutations in CNNM2 lead to renal Mg^2+ wasting and severe hypomagnesemia, with clinical manifestations including muscle weakness, seizures, and neurodevelopmental delay. CNNM2 is implicated in blood pressure regulation, electrolyte balance, and possibly in cancer via protein-protein interactions. The crystal structure reveals domains essential for dimerization and Mg^2+ efflux. CNNM2 does not currently have specific pharmacologic modulators in clinical use, but serum Mg^2+ is a key disease biomarker. Safety concerns center on electrolyte disturbance if the target is modulated. Key structural features: - N-terminal extracellular domain - Four transmembrane segments (DUF21) - Two CBS domains (CBS1, CBS2) - C-terminal cyclic nucleotide-binding homology (CNBH) domain Principal tissue expression: - Kidney (distal convoluted tubule) - Brain - Also expressed in lung Disease relevance: - Mutations cause hypomagnesemia and neurological impairment - Associated with hypertension, coronary artery disease, and possible cancer promotion via PRL protein interactions Therapeutic challenge: - Targeting CNNM2 must consider risk of Mg^2+ homeostasis disruption and downstream systemic effects

Other names

CNNM2Metal transporter CNNM2Ancient conserved domain-containing protein 2 (ACDP2)Cyclin-M2HOMG6HOMGSMRSLC70A2Q9H8M5CNNM2phCNNM2

Drugs or interventions (e.g., magnesium supplements) compensate for CNNM2-mediated Mg^2+ transport deficits. No specific direct small-molecule or biologic modulator mechanism described for CNNM2 yet.