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Channel Function is Dissociated from the Intrinsic Kinase Activity and Autophosphorylation of TRPM7/ChaK1
The Journal of Biological Chemistry
  • Masayuki Matsushita
  • J. Ashot Kozak, Wright State University - Main Campus
  • Yoshio Shimizu
  • Derek T. McLachlin
  • Hiroto Yamaguchi
  • Fan-Yan Wei
  • Kazuhito Tomizawa
  • Hideki Matsui
  • Brian T. Chait
  • Michael D. Cahalan
  • Angus C. Nairn
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TRPM7/ChaK1 is a unique channel/kinase that contains a TRPM channel domain with 6 transmembrane segments fused to a novel serine-threonine kinase domain at its C terminus. The goal of this study was to investigate a possible role of kinase activity and autophosphorylation in regulation of channel activity of TRPM7/ChaK1. Residues essential for kinase activity were identified by site-directed mutagenesis. Two major sites of autophosphorylation were identified in vitro by mass spectrometry at Ser(1511) and Ser(1567), and these sites were found to be phosphorylated in intact cells. TRPM7/ChaK1 is a cation-selective channel that exhibits strong outward rectification and inhibition by millimolar levels of internal [Mg(2+)]. Mutation of the two autophosphorylation sites or of a key catalytic site that abolished kinase activity did not alter channel activity measured by whole-cell recording or Ca(2+) influx. Inhibition by internal Mg(2+) was also unaffected in the autophosphorylation site or "kinase-dead" mutants. Moreover, kinase activity was enhanced by Mg(2+), was decreased by Zn(2+), and was unaffected by Ca(2+). In contrast, channel activity was inhibited by all three of these divalent cations. However, deletion of much of C-terminal kinase domain resulted in expression of an apparently inactive channel. We conclude that neither current activity nor regulation by internal Mg(2+) is affected by kinase activity or autophosphorylation but that the kinase domain may play a structural role in channel assembly or subcellular localization.
Citation Information
Masayuki Matsushita, J. Ashot Kozak, Yoshio Shimizu, Derek T. McLachlin, et al.. "Channel Function is Dissociated from the Intrinsic Kinase Activity and Autophosphorylation of TRPM7/ChaK1" The Journal of Biological Chemistry Vol. 280 Iss. 21 (2005) p. 20793 - 20803 ISSN: 1083-351X
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