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TRPM6

Function

Bifunctional protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain (PubMed:14576148, PubMed:16636202, PubMed:18258429, PubMed:18365021). Crucial for Mg(2+) homeostasis. Has an important role in epithelial Mg(2+) transport and in the active Mg(2+) absorption in the gut and kidney (PubMed:14576148). However, whether TRPM6 forms functional homomeric channels by itself or functions primarily as a subunit of heteromeric TRPM6-TRPM7 channels, is still under debate (PubMed:14576148, PubMed:16636202, PubMed:24385424).

TRPM6 kinase, cleaved form

The C-terminal kinase domain can be cleaved from the channel segment in a cell-type-specific fashion. The cleaved kinase fragments can translocate to the nucleus, and bind chromatin-remodeling complex proteins to ultimately phosphorylate specific Ser/Thr residues of histones known to be functionally important for cell differentiation and development.

Involvement in disease

Hypomagnesemia 1

HOMG1

A disorder due to a primary defect in intestinal magnesium absorption. It is characterized by low levels of serum magnesium alongside with a normal renal magnesium secretion, secondary hypocalcemia and calcinocis. Affected individuals show neurologic symptoms of hypomagnesemic hypocalcemia, including seizures and muscle spasms, during infancy. Hypocalcemia is secondary to parathyroid failure resulting from magnesium deficiency. Untreated, the disorder may be fatal or may result in neurological damage.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Autophosphorylated; autophosphorylation controlls the protein kinase activity of TRPM6 towards their substrates (PubMed:18258429, PubMed:18365021). Autophosphorylation of Thr-1851 in the kinase domain is essential for the inhibitory effect of RACK1 (PubMed:18258429).

The C-terminus of TRPM6 is proteolytically cleaved in vivo, in a cell type-specific fashion, releasing the kinase module from the transmembrane domain. The cleaved kinase fragments are translocated to the nucleus to phosphorylate histones and regulate gene expression.

Sequence Similarities

In the C-terminal section; belongs to the protein kinase superfamily. Alpha-type protein kinase family. ALPK subfamily.

In the N-terminal section; belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM6 sub-subfamily.

Tissue Specificity

Highly expressed in kidney and colon. Isoform TRPM6a and isoform TRPM6b, are coexpressed with TRPM7 in kidney, and testis, and are also found in several cell lines of lung origin. Isoform TRPM6c is detected only in testis and in NCI-H510A small cell lung carcinoma cells.

Cellular localization

Alternative names

CHAK2, TRPM6, Transient receptor potential cation channel subfamily M member 6, Channel kinase 2, Melastatin-related TRP cation channel 6

swissprot:Q9BX84 entrezGene:140803 swissprot:Q96LV9 swissprot:Q5VYG5 omim:607009