Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 3408K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JGP Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Demeuse, P. Articles by Fleig, A. Search for Related Content PubMed PubMed Citation Articles by Demeuse, P. Articles by Fleig, A. Social Bookmarking                      What's this?

Laboratory of Cell and Molecular Signaling, Center for Biomedical Research at The Queen's Medical Center and John A. Burns School of Medicine at the University of Hawaii, Honolulu, HI 96813

Correspondence to Andrea Fleig: afleig{at}hawaii.edu

TRPM7 is a Ca²⁺- and Mg²⁺-permeable cation channel that also contains a protein kinase domain. While there is general consensus that the channel is inhibited by free intracellular Mg²⁺, the functional roles of intracellular levels of Mg·ATP and the kinase domain in regulating TRPM7 channel activity have been discussed controversially. To obtain insight into these issues, we have determined the effect of purine and pyrimidine magnesium nucleotides on TRPM7 currents and investigated the possible involvement of the channel's kinase domain in mediating them. We report here that physiological Mg·ATP concentrations can inhibit TRPM7 channels and strongly enhance the channel blocking efficacy of free Mg²⁺. Mg·ADP, but not AMP, had similar, albeit smaller effects, indicating a double protection against possible Mg²⁺ and Ca²⁺ overflow during variations of cell energy levels. Furthermore, nearly all Mg-nucleotides were able to inhibit TRPM7 activity to varying degrees with the following rank in potency: ATP > TTP > CTP GTP UTP > ITP free Mg²⁺ alone. These nucleotides also enhanced TRPM7 inhibition by free Mg²⁺, suggesting the presence of two interacting binding sites that jointly regulate TRPM7 channel activity. Finally, the nucleotide-mediated inhibition was lost in phosphotransferase-deficient single-point mutants of TRPM7, while the Mg²⁺-dependent regulation was retained with reduced efficacy. Interestingly, truncated mutant channels with a complete deletion of the kinase domain regained Mg·NTP sensitivity; however, this inhibition did not discriminate between nucleotide species, suggesting that the COOH-terminal truncation exposes the previously inaccessible Mg²⁺ binding site to Mg-nucleotide binding without imparting nucleotide specificity. We conclude that the nucleotide-dependent regulation of TRPM7 is mediated by the nucleotide binding site on the channel's endogenous kinase domain and interacts synergistically with a Mg²⁺ binding site extrinsic to that domain.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				A. Goytain, R. M. Hines, and G. A. Quamme Huntingtin-interacting Proteins, HIP14 and HIP14L, Mediate Dual Functions, Palmitoyl Acyltransferase and Mg2+ Transport J. Biol. Chem., November 28, 2008; 283(48): 33365 - 33374. [Abstract] [Full Text] [PDF]

				S. Thebault, G. Cao, H. Venselaar, Q. Xi, R. J. M. Bindels, and J. G. J. Hoenderop Role of the {alpha}-Kinase Domain in Transient Receptor Potential Melastatin 6 Channel and Regulation by Intracellular ATP J. Biol. Chem., July 18, 2008; 283(29): 19999 - 20007. [Abstract] [Full Text] [PDF]

				M. Mederos y Schnitzler, J. Waring, T. Gudermann, and V. Chubanov Evolutionary determinants of divergent calcium selectivity of TRPM channels FASEB J, May 1, 2008; 22(5): 1540 - 1551. [Abstract] [Full Text] [PDF]

				R. M. Touyz Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1103 - H1118. [Abstract] [Full Text] [PDF]

				M. Dattilo, N. J. Penington, and K. Williams Inhibition of TRPC5 Channels by Intracellular ATP Mol. Pharmacol., January 1, 2008; 73(1): 42 - 49. [Abstract] [Full Text] [PDF]

				R. A. Nichols, A. F. Dengler, E. M. Nakagawa, M. Bashkin, B. T. Paul, J. Wu, and G. M. Khan A Constitutive, Transient Receptor Potential-like Ca2+ Influx Pathway in Presynaptic Nerve Endings Independent of Voltage-gated Ca2+ Channels and Na+/Ca2+ Exchange J. Biol. Chem., December 7, 2007; 282(49): 36102 - 36111. [Abstract] [Full Text] [PDF]

				M. Li, J. Du, J. Jiang, W. Ratzan, L.-T. Su, L. W. Runnels, and L. Yue Molecular Determinants of Mg2+ and Ca2+ Permeability and pH Sensitivity in TRPM6 and TRPM7 J. Biol. Chem., August 31, 2007; 282(35): 25817 - 25830. [Abstract] [Full Text] [PDF]

				B. F. Bessac and A. Fleig TRPM7 channel is sensitive to osmotic gradients in human kidney cells J. Physiol., August 1, 2007; 582(3): 1073 - 1086. [Abstract] [Full Text] [PDF]

				V. Chubanov, K. P. Schlingmann, J. Waring, J. Heinzinger, S. Kaske, S. Waldegger, M. M. y Schnitzler, and T. Gudermann Hypomagnesemia with Secondary Hypocalcemia due to a Missense Mutation in the Putative Pore-forming Region of TRPM6 J. Biol. Chem., March 9, 2007; 282(10): 7656 - 7667. [Abstract] [Full Text] [PDF]

				M. Langeslag, K. Clark, W. H. Moolenaar, F. N. van Leeuwen, and K. Jalink Activation of TRPM7 Channels by Phospholipase C-coupled Receptor Agonists J. Biol. Chem., January 5, 2007; 282(1): 232 - 239. [Abstract] [Full Text] [PDF]

				R. C. Hardie TRP channels and lipids: from Drosophila to mammalian physiology J. Physiol., January 1, 2007; 578(1): 9 - 24. [Abstract] [Full Text] [PDF]

				A. Gwanyanya, K. R. Sipido, J. Vereecke, and K. Mubagwa ATP and PIP2 dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes Am J Physiol Cell Physiol, October 1, 2006; 291(4): C627 - C635. [Abstract] [Full Text] [PDF]

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents