title: TRPM7 is a molecular substrate of ATP-evoked P2X7-like currents in tumor cells.
abstract: Within the ion channel-coupled purine receptor (P2X) family, P2X7 has gained particular interest because of its role in immune responses and in the growth control of several malignancies. Typical hallmarks of P2X7 are nonselective and noninactivating cation currents that are elicited by high concentrations (0.1-10 mM) of extracellular ATP. Here, we observe spurious ATP-induced currents in HEK293 cells that neither express P2X7 nor display ATP-induced Ca(2+) influx or Yo-Pro-1 uptake. Although the biophysical properties of these ionic currents resemble those of P2X7 in terms of their reversal potential close to 0 mV, nonrectifying current-voltage relationship, current run-up during repeated ATP application, and augmentation in bath solutions containing low divalent cation (DIC) concentrations, they are poorly inhibited by established P2X7 antagonists. Because high ATP concentrations reduce the availability of DICs, these findings prompted us to ask whether other channel entities may become activated by our experimental regimen. Indeed, a bath solution with no added DICs yields similar currents and also a rapidly inactivating Na(+)-selective conductance. We provide evidence that TRPM7 and ASIC1a (acid-sensing ion channel type Ia)-like channels account for these noninactivating and phasic current components, respectively. Furthermore, we find ATP-induced currents in rat C6 glioma cells, which lack functional P2X receptors but express TRPM7. Thus, the observation of an atypical P2X7-like conductance may be caused by the activation of TRPM7 by ATP, which scavenges free DICs and thereby releases TRPM7 from permeation block. Because TRPM7 has a critical role in controlling the intracellular Mg(2+) homeostasis and regulating tumor growth, these data imply that the proposed role of P2X7 in C6 glioma cell proliferation deserves reevaluation.
authors.affiliation: Rudolf Boehm Institute of Pharmacology and Toxicology, Medical Faculty, Leipzig University, 04107 Leipzig, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Nörenberg
authors.affiliation: Rudolf Boehm Institute of Pharmacology and Toxicology, Medical Faculty, Leipzig University, 04107 Leipzig, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Plötz
authors.affiliation: Rudolf Boehm Institute of Pharmacology and Toxicology, Medical Faculty, Leipzig University, 04107 Leipzig, Germany.
authors.forename: Helga
authors.initials: H
authors.lastname: Sobottka
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, 80336 Munich, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Chubanov
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, 80336 Munich, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Mittermeier
authors.affiliation: Rudolf Boehm Institute of Pharmacology and Toxicology, Medical Faculty, Leipzig University, 04107 Leipzig, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Kalwa
authors.affiliation: Rudolf Boehm Institute of Pharmacology and Toxicology, Medical Faculty, Leipzig University, 04107 Leipzig, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Aigner
authors.affiliation: Rudolf Boehm Institute of Pharmacology and Toxicology, Medical Faculty, Leipzig University, 04107 Leipzig, Germany michael.schaefer@medizin.uni-leipzig.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Schaefer
mesh_terms: D000200:Action Potentials; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D005910:Glioma / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: C546468:P2RX7 protein, human; D058486:Receptors, Purinergic P2X7; D050053:TRPM Cation Channels; D000255:Adenosine Triphosphate; C486584:Trpm7 protein, rat; D008274:Magnesium; D002118:Calcium