HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 91/4/1556    most recent 00676.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science 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 Web of Science (29) Citing Articles via Google Scholar Google Scholar Articles by Vijayaragavan, K. Articles by Chahine, M. Search for Related Content PubMed PubMed Citation Articles by Vijayaragavan, K. Articles by Chahine, M.

Modulation of Na_v1.7 and Na_v1.8 Peripheral Nerve Sodium Channels by Protein Kinase A and Protein Kinase C

¹ Laval University, Department of Medicine, Sainte Foy, Quebec, G1V 4G5, Canada; ² Molecular and Cellular Cardiology Program, Veterans Affairs New York Harbor Healthcare System, State University of New York Downstate Medical Center at Brooklyn and New York University School of Medicine, New York City, New York 10010

Submitted 14 July 2003; accepted in final form 25 November 2003

Voltage-gated Na⁺ channels (VGSC) are transmembrane proteins that are essential for the initiation and propagation of action potentials in neuronal excitability. Because neurons express a mixture of Na⁺ channel isoforms and protein kinase C (PKC) isozymes, the nature of which channel is being regulated by which PKC isozyme is not known. We showed that DRG VGSC Na_v1.7 (TTX-sensitive) and Na_v1.8 (TTX-resistant), expressed in Xenopus oocytes were differentially regulated by protein kinase A (PKA) and PKC isozymes using the two-electrode voltage-clamp method. PKA activation resulted in a dose-dependent potentiation of Na_v1.8 currents and an attenuation of Na_v1.7 currents. PKA-induced increases (Na_v1.8) and decreases (Na_v1.7) in peak currents were not associated with shifts in voltage-dependent activation or inactivation. The PKA-mediated increase in Na_v1.8 current amplitude was prevented by chloroquine, suggesting that cell trafficking may contribute to the changes in Na_v1.8 current amplitudes. A dose-dependent decrease in Na_v1.7 and Na_v1.8 currents was observed with the PKC activators phorbol 12-myristate, 13-acetate (PMA) and phorbol 12,13-dibutyrate. PMA induced shifts in the steady-state activation of Na_v1.7 and Na_v1.8 channels by 6.5 and 14 mV, respectively, in the depolarizing direction. The role of individual PKC isozymes in the regulation of Na_v1.7 and Na_v1.8 was determined using PKC-isozyme-specific peptide activators and inhibitors. The decrease in the Na_v1.8 peak current induced by PMA was prevented by a specific PKC isozyme peptide antagonist, whereas the PMA effect on Na_v1.7 was prevented by PKC and IIPKC peptide inhibitors. The data showed that Na_v1.7 and Na_v1.8 were differentially modulated by PKA and PKC. This is the first report demonstrating a functional role for PKC and IIPKC in the regulation of Na_v1.7 and Na_v1.8 Na⁺ channels. Identification of the particular PKC isozymes(s) that mediate the regulation of Na⁺ channels is essential for understanding the molecular mechanism involved in neuronal ion channel regulation in normal and pathological conditions.

This article has been cited by other articles:

				A. Chatelier, L. Dahllund, A. Eriksson, J. Krupp, and M. Chahine Biophysical Properties of Human Nav1.7 Splice Variants and Their Regulation by Protein Kinase A J Neurophysiol, May 1, 2008; 99(5): 2241 - 2250. [Abstract] [Full Text] [PDF]

				A. Hudmon, J.-S. Choi, L. Tyrrell, J. A. Black, A. M. Rush, S. G. Waxman, and S. D. Dib-Hajj Phosphorylation of Sodium Channel Nav1.8 by p38 Mitogen-Activated Protein Kinase Increases Current Density in Dorsal Root Ganglion Neurons J. Neurosci., March 19, 2008; 28(12): 3190 - 3201. [Abstract] [Full Text] [PDF]

				R. De Col, K. Messlinger, and R. W. Carr Conduction velocity is regulated by sodium channel inactivation in unmyelinated axons innervating the rat cranial meninges J. Physiol., February 15, 2008; 586(4): 1089 - 1103. [Abstract] [Full Text] [PDF]

				J. A. R. Ostman, M. A. Nassar, J. N. Wood, and M. D. Baker GTP up-regulated persistent Na+ current and enhanced nociceptor excitability require NaV1.9 J. Physiol., February 15, 2008; 586(4): 1077 - 1087. [Abstract] [Full Text] [PDF]

				W. P. Few, T. Scheuer, and W. A. Catterall Dopamine modulation of neuronal Na+ channels requires binding of A kinase-anchoring protein 15and PKA by a modified leucine zipper motif PNAS, March 20, 2007; 104(12): 5187 - 5192. [Abstract] [Full Text] [PDF]

				F. Amaya, H. Wang, M. Costigan, A. J. Allchorne, J. P. Hatcher, J. Egerton, T. Stean, V. Morisset, D. Grose, M. J. Gunthorpe, et al. The Voltage-Gated Sodium Channel Nav1.9 Is an Effector of Peripheral Inflammatory Pain Hypersensitivity J. Neurosci., December 13, 2006; 26(50): 12852 - 12860. [Abstract] [Full Text] [PDF]

				P. L. Sheets, P. Gerner, C.-F. Wang, S.-Y. Wang, G. K. Wang, and T. R. Cummins Inhibition of Nav1.7 and Nav1.4 Sodium Channels by Trifluoperazine Involves the Local Anesthetic Receptor J Neurophysiol, October 1, 2006; 96(4): 1848 - 1859. [Abstract] [Full Text] [PDF]

				W. J. Brackenbury and M. B. A. Djamgoz Activity-dependent regulation of voltage-gated Na+ channel expression in Mat-LyLu rat prostate cancer cell line J. Physiol., June 1, 2006; 573(2): 343 - 356. [Abstract] [Full Text] [PDF]

				J.-Y. Lou, F. Laezza, B. R. Gerber, M. Xiao, K. A. Yamada, H. Hartmann, A. M. Craig, J. M. Nerbonne, and D. M. Ornitz Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels J. Physiol., November 15, 2005; 569(1): 179 - 193. [Abstract] [Full Text] [PDF]

				E. K. Wittmack, A. M. Rush, A. Hudmon, S. G. Waxman, and S. D. Dib-Hajj Voltage-Gated Sodium Channel Nav1.6 Is Modulated by p38 Mitogen-Activated Protein Kinase J. Neurosci., July 13, 2005; 25(28): 6621 - 6630. [Abstract] [Full Text] [PDF]

				M. A. Nassar, L. C. Stirling, G. Forlani, M. D. Baker, E. A. Matthews, A. H. Dickenson, and J. N. Wood Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain PNAS, August 24, 2004; 101(34): 12706 - 12711. [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]

				S. Hong, T. J. Morrow, P. E. Paulson, L. L. Isom, and J. W. Wiley Early Painful Diabetic Neuropathy Is Associated with Differential Changes in Tetrodotoxin-sensitive and -resistant Sodium Channels in Dorsal Root Ganglion Neurons in the Rat J. Biol. Chem., July 9, 2004; 279(28): 29341 - 29350. [Abstract] [Full Text] [PDF]