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

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.051086v1 306/2/498    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 Zhou, X. Articles by Priestley, T. Search for Related Content PubMed PubMed Citation Articles by Zhou, X. Articles by Priestley, T.

NEUROPHARMACOLOGY

Vinpocetine Is a Potent Blocker of Rat Na_V1.8 Tetrodotoxin-Resistant Sodium Channels

CNS/CV Biological Research, Schering-Plough Research Institute, Kenilworth, New Jersey

Vinpocetine is a clinically used synthetic vincamine derivative with a diverse pharmacological profile that includes action at several ion channels, principally "generic" populations of sodium channels that give rise to tetrodotoxin-sensitive conductances. A number of cell types are known to express tetrodotoxin-resistant (TTXr) sodium conductances, the molecular bases of which have remained elusive until recently. One such TTXr channel, termed Na_V1.8, is of particular interest because of its prominent and selective expression in peripheral afferent nerves. The effects of vinpocetine on TTXr channels specifically, are unknown. We have assessed the effects of the drug on cloned rat Na_V1.8 channels expressed in a dorsal root ganglion-derived cell line, ND7/23. Vinpocetine produced a concentration- and state-dependent inhibition of Na_V1.8 sodium channel activity. Voltage-clamp experiments revealed an 3-fold increase in vinpocetine potency when whole-cell Na_V1.8 conductances were elicited from relatively depolarized potentials (–35 mV; IC₅₀ = 3.5 µM) compared with hyperpolarized holding potentials (–90 mV; IC₅₀ = 10.4 µM). Vinpocetine also produced an 22 mV leftward shift in the voltage dependence of Na_V1.8 channel inactivation but did not affect the voltage range of channel activation. These properties are reminiscent of several other known sodium channel blockers and suggested that vinpocetine may exhibit frequency-dependent block. Accordingly, tonic block of Na_V1.8 channels by vinpocetine (3 µM) increased proportionally with increasing depolarizing commands over the frequency range 0.1 to 1Hz. In summary, the present data demonstrate that vinpocetine is capable of blocking Na_V1.8 sodium channel activity and suggest a potential additional utility in various sensory abnormalities arising from abnormal peripheral nerve activity.

Address correspondence to: Dr. Tony Priestley, CNS/CV Biological Research, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033. E-mail: tony.priestley{at}spcorp.com

This article has been cited by other articles:

				L. M. Sharkey, X. Cheng, V. Drews, D. A. Buchner, J. M. Jones, M. J. Justice, S. G. Waxman, S. D. Dib-Hajj, and M. H. Meisler The ataxia3 Mutation in the N-Terminal Cytoplasmic Domain of Sodium Channel Nav1.6 Disrupts Intracellular Trafficking J. Neurosci., March 4, 2009; 29(9): 2733 - 2741. [Abstract] [Full Text] [PDF]

				M. Seda, F. M Pinto, S. Wray, C. G Cintado, P. Noheda, H. Buschmann, and L. Candenas Functional and Molecular Characterization of Voltage-Gated Sodium Channels in Uteri from Nonpregnant Rats Biol Reprod, November 1, 2007; 77(5): 855 - 863. [Abstract] [Full Text] [PDF]

				J. Zhao, R. Ziane, A. Chatelier, M. E. O'Leary, and M. Chahine Lidocaine Promotes the Trafficking and Functional Expression of Nav1.8 Sodium Channels in Mammalian Cells J Neurophysiol, July 1, 2007; 98(1): 467 - 477. [Abstract] [Full Text] [PDF]

				A. E. Medina, T. E. Krahe, and A. S. Ramoa Restoration of Neuronal Plasticity by a Phosphodiesterase Type 1 Inhibitor in a Model of Fetal Alcohol Exposure J. Neurosci., January 18, 2006; 26(3): 1057 - 1060. [Abstract] [Full Text] [PDF]

				J. J. Devaux and S. S. Scherer Altered Ion Channels in an Animal Model of Charcot-Marie-Tooth Disease Type IA J. Neurosci., February 9, 2005; 25(6): 1470 - 1480. [Abstract] [Full Text] [PDF]

				E. K. Wittmack, A. M. Rush, M. J. Craner, M. Goldfarb, S. G. Waxman, and S. D. Dib-Hajj Fibroblast Growth Factor Homologous Factor 2B: Association with Nav1.6 and Selective Colocalization at Nodes of Ranvier of Dorsal Root Axons J. Neurosci., July 28, 2004; 24(30): 6765 - 6775. [Abstract] [Full Text] [PDF]