Selective internalization of sodium channels in rat dorsal root ganglion neurons infected with herpes simplex virus-1

Nina Storey¹, David Latchman², and Stuart Bevan¹

¹ Novartis Institute for Medical Sciences, London WC1E 6BS, UK
² Windeyer Department of Molecular Pathology, University College London Medical School, The Windeyer Institute of Medical Sciences, London W1P 6DB, UK

Address correspondence to Nina Storey at her present address, National Institute of Environmental Health Sciences, 111 Alexander Dr., PO Box 12233, Mail Drop F205, Research Triangle Park, NC 27709. Tel.: (919) 541-0287. Fax: (919) 541-1431. E-mail: storey{at}niehs.nih.gov

Abstract: The neurotropic virus, herpes simplex type 1 (HSV-1), inhibits the excitability of peripheral mammalian neurons, but the molecular mechanism of this effect has not been identified. Here, we use voltage-clamp measurement of ionic currents and an antibody against sodium channels to show that loss of excitability results from the selective, precipitous, and complete internalization of voltage-activated sodium channel proteins from the plasma membrane of neurons dissociated from rat dorsal root ganglion. The internalization process requires viral protein synthesis but not viral encapsulation, and does not alter the density of voltage-activated calcium or potassium channels. However, internalization is blocked completely when viruses lack the neurovirulence factor, infected cell protein 34.5, or when endocytosis is inhibited with bafilomycin A₁ or chloroquine. Although it has been recognized for many years that viruses cause cell pathology by interfering with signal transduction pathways, this is the first example of viral pathology resulting from selective internalization of an integral membrane protein. In studying the HSV-induced redistribution of sodium channels, we have uncovered a previously unknown pathway for the rapid and dynamic control of excitability in sensory neurons by internalization of sodium channels.

Key Words: voltage-gated sodium channels; sensory neurons; sodium channel regulation; calcium channels; potassium channels

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