title: Imatinib-mesylate blocks recombinant T-type calcium channels expressed in human embryonic kidney-293 cells by a protein tyrosine kinase-independent mechanism.
abstract: The 2-phenylaminopyrimidine derivative imatinib-mesylate, a powerful protein tyrosine kinase (PTK) inhibitor that targets abl, c-kit, and the platelet-derived growth factor receptors, is rapidly gaining a relevant role in the treatment of several types of neoplasms. Because first generation PTK inhibitors affect the activity of a large number of voltage-dependent ion channels, the present study explored the possibility that imatinib-mesylate could interfere with the activity of T-type channels, a class of voltage-dependent Ca2+ channels that take part in the chain of events elicited by PTK activation. The effect of the drug on T-type channel activity was examined using the whole-cell patch-clamp technique with Ba2+ (10 mM) as the permeant ion in human embryonic kidney-293 cells, stably expressing the rat Ca(V)3.3 channels. Imatinib-mesylate concentrations, ranging from 30 to 300 microM, reversibly decreased Ca(V)3.3 current amplitude with an IC(50) value of 56.9 microM. By contrast, when imatinib-mesylate (500 microM) was intracellularly dialyzed with the pipette solution, no reduction in Ba2+ current density was observed. The 2-phenylaminopyrimidine derivative modified neither the voltage dependence of activation nor the steady-state inactivation of Ca(V)3.3 channels. The decrease in extracellular Ba2+ concentration from 10 to 2 mM and the substitution of Ca2+ for Ba2+ increased the extent of 30 microM imatinib-mesylate-induced percentage of channel blockade from 25.9 +/- 2.4 to 36.3 +/- 0.9% in 2 mM Ba2+ and 44.2 +/- 2.3% in 2 mM Ca2+. In conclusion, imatinib-mesylate blocked the cloned Ca(V)3.3 channels by a PTK-independent mechanism. Specifically, the drug did not affect the activation or the inactivation of the channel but interfered with the ion permeation process.
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Federico II University of Naples, Via Pansini no. 5, 80131 Naples, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Cataldi
authors.forename: Annarita
authors.initials: A
authors.lastname: Gaudino
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lariccia
authors.forename: Michela
authors.initials: M
authors.lastname: Russo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Amoroso
authors.forename: Gianfranco
authors.initials: G
authors.lastname: di Renzo
authors.forename: Lucio
authors.initials: L
authors.lastname: Annunziato
mesh_terms: D001549:Benzamides; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004338:Drug Combinations; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D007668:Kidney / Q000166:cytology; D026901:Membrane Transport Proteins; D008698:Mesylates / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D001549:Benzamides; C469757:CACNA1I protein, human; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; D008698:Mesylates; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases