Transient receptor potential cation channel subfamily M member 6 and 7 (TRPM6/TRPM7)

Transient receptor potential cation channel subfamily M member 6 (TRPM6) and member 7 (TRPM7) are unique bifunctional proteins, often referred to as chanzymes because they consist of an ion channel domain fused to a C-terminal alpha-kinase domain (UniProt Q9BX84, Q96QT4). These channels are primarily permeable to divalent cations, particularly magnesium (Mg2+) and calcium (Ca2+), and they play a fundamental role in maintaining systemic and cellular magnesium homeostasis (PubMed: 11385574). TRPM6 is predominantly expressed in the epithelial cells of the intestine and the distal convoluted tubule of the kidney, where it facilitates magnesium absorption and reabsorption; mutations in TRPM6 cause hypomagnesemia with secondary hypocalcemia (HSH) (PubMed: 12032569). In contrast, TRPM7 is ubiquitously expressed and is vital for cell viability, proliferation, and migration, with its dysregulation linked to various cancers, cardiovascular diseases, and neuronal death following ischemic stroke (PubMed: 21841151). Pharmacological targeting of these channels involves small molecule inhibitors like Waixenicin A and NS8593, which are being explored for their potential in treating magnesium-related disorders and inhibiting tumor progression (PubMed: 20610562). However, the widespread physiological roles of TRPM7 present significant challenges for achieving therapeutic selectivity without inducing systemic toxicity.

Other names

Melastatin-6Melastatin-7CHAK2CHAK1Channel-kinase 1Channel-kinase 2TRP-PLIKLTrPC7HSH

Inhibition of cation conductance through the channel pore or modulation of the C-terminal alpha-kinase activity to regulate downstream signaling pathways.