QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.061184v1 309/1/208    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cataldi, M. Articles by Annunziato, L. Search for Related Content PubMed PubMed Citation Articles by Cataldi, M. Articles by Annunziato, L.

CELLULAR AND MOLECULAR

Imatinib-Mesylate Blocks Recombinant T-Type Calcium Channels Expressed in Human Embryonic Kidney-293 Cells by a Protein Tyrosine Kinase-Independent Mechanism

Division of Pharmacology, Department of Neuroscience, Federico II, University of Naples, Naples, Italy

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_V3.3 channels. Imatinib-mesylate concentrations, ranging from 30 to 300 µM, reversibly decreased Ca_V3.3 current amplitude with an IC₅₀ value of 56.9 µM. By contrast, when imatinib-mesylate (500 µM) 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_V3.3 channels. The decrease in extracellular Ba²⁺ concentration from 10 to 2 mM and the substitution of Ca²⁺ for Ba²⁺ increased the extent of 30 µM 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_V3.3 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.

Address correspondence to: Dr. Lucio Annunziato, Division of Pharmacology, Department of Neuroscience, Federico II University of Naples, Via Pansini no. 5, 80131 Naples, Italy. E-mail: lannunzi{at}unina.it

This article has been cited by other articles:

				M. Cataldi, V. Lariccia, V. Marzaioli, A. Cavaccini, G. Curia, D. Viggiano, L.M.T. Canzoniero, G. di Renzo, M. Avoli, and L. Annunziato Zn2+ Slows Down CaV3.3 Gating Kinetics: Implications for Thalamocortical Activity J Neurophysiol, October 1, 2007; 98(4): 2274 - 2284. [Abstract] [Full Text] [PDF]