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J. Biol. Chem., Vol. 282, Issue 1, 232-239, January 5, 2007

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Activation of TRPM7 Channels by Phospholipase C-coupled Receptor Agonists^*

Michiel Langeslag, Kristopher Clark, Wouter H. Moolenaar^¶, Frank N. van Leeuwen^¶, and Kees Jalink¹

From the Divisions of Cell Biology, and ^¶Cellular Biochemistry, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam and Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Center P.O. Box 9101, 6500 HB Nijmegen, The Netherlands

TRPM7 is a ubiquitously expressed nonspecific cation channel that has been implicated in cellular Mg²⁺ homeostasis. We have recently shown that moderate overexpression of TRPM7 in neuroblastoma N1E-115 cells elevates cytosolic Ca²⁺ levels and enhances cell-matrix adhesion. Furthermore, activation of TRPM7 by phospholipase C (PLC)-coupled receptor agonists caused a further increase in intracellular Ca²⁺ levels and augmented cell adhesion and spreading in a Ca²⁺-dependent manner (1). Regulation of the TRPM7 channel is not well understood, although it has been reported that PIP₂ hydrolysis closes the channel. Here we have examined the regulation of TRPM7 by PLC-coupled receptor agonists such as bradykinin, lysophosphatidic acid, and thrombin. Using FRET assays for second messengers, we have shown that the TRPM7-dependent Ca²⁺ increase closely correlates with activation of PLC. Under non-invasive "perforated patch clamp" conditions, we have found similar activation of TRPM7 by PLC-coupled receptor agonists. Although we could confirm that, under whole-cell conditions, the TRPM7 currents were significantly inhibited following PLC activation, this PLC-dependent inhibition was only observed when [Mg²⁺]_i was reduced below physiological levels. Thus, under physiological ionic conditions, TRPM7 currents were activated rather than inhibited by PLC-activating receptor agonists.

Received for publication, June 2, 2006 , and in revised form, November 3, 2006.

^* This work was supported by The Dutch Cancer Society. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data, references, Figs. S1–S4, and Table S1.

¹ To whom correspondence should be addressed: Division of Cell Biology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel.: 31-20-5121933; Fax: 31-20-5121944; E-mail: K.Jalink{at}NKI.nl.

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