Selective internalization of sodium channels in rat dorsal root ganglion neurons infected with herpes simplex virus-1.
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 A(1) 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.
D000200:Action Potentials; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000821:virology; D006561:Herpes Simplex / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D018942:Macrolides; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000821:virology; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation
D000900:Anti-Bacterial Agents; D000962:Antimalarials; D004791:Enzyme Inhibitors; D018942:Macrolides; D015222:Sodium Channels; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; D002738:Chloroquine; C040929:bafilomycin A1; D006180:Proton-Translocating ATPases