The TRPM6 Kinase Domain Determines the Mg·ATP Sensitivity of TRPM7/M6 Heteromeric Ion Channels

Abstract

Background: TRPM6 and TRPM7 combine ion channel and ␣-kinase functions. Results: ATP inhibits TRPM7 but not TRPM6 or heteromeric TRPM6/M7 channels. Disruption of phosphorylation activity of TRPM6 kinase re-establishes ATP sensitivity to heteromeric channels. Conclusion: TRPM6 uncouples heteromeric channels from cellular energy levels. Significance: The altered characteristics of TRPM6/M7 compared with homomeric TRPM7 may enhance Ca 2ϩ and Mg

Structures of the calcium-activated, non-selective cation channel TRPM4

“…6), explaining the lack of ATP inhibition in TRPM5 33 . The ATP inhibition in TRPM4 is also distinct from that in TRPM6/7 34,35 . TRPM6/7 is inhibited by Mg-ATP, but not free ATP, and the inhibition likely involves the C-terminal kinase domain that is absent in TRPM4.…”

Magnesium in Man: Implications for Health and Disease

“…TRPM6 contains six transmembrane spanning domains with a pore region between the fifth and sixth segment and a large kinase domain fused to the channel's intracellular COOH terminus. TRPM6 may function in homo-and heteromeric tetramers with TRPM7, al-though there is some controversy about the necessity of TRPM7 for TRPM6 function (314,588).…”

Regulation of Mg2+ Reabsorption and Transient Receptor Potential Melastatin Type 6 Activity by cAMP Signaling

“…4,14,15 Intracellular Mg 2+ reduces TRPM6 activity, with reported affinities between 0.02 and 1 mM. 4,16,17 In addition, TRPM6 is modulated by intracellular and extracellular pH, 15,18 halides, 19 oxidation, 20 phosphatidylinositol 4,5-bisphosphate (PIP 2 ), 21 flavaglines, 22 and sphingolipids. 23 TRPM6 channels comprise a C-terminal serine/threonine a-kinase domain, the function of which and its link to the channel activity is incompletely understood.…”

“…4,6,16,17,19,24 TRPM6 undergoes autophosphorylation, 24,25 which leads to a shift in the inhibition by intracellular Mg 2+ /Mg 2+ nucleotides to higher concentrations. 17 In the kidneys, TRPM6 is regulated by the EGF, [26][27][28] insulin, 29 estrogens, 30,31 purinergic signaling, 32 dietary Mg 2+ intake, 30 and acid-base status. 33 Previous studies have suggested increased DCT Mg 2+ reabsorption in response to hormones such as parathyroid hormone (PTH), glucagon, calcitonin, and arginine vasopressin.…”