Sodium channel activity modulates multiple functions in microglia.
Microglia provide surveillance in the central nervous system and become activated following tissue insult. Detailed mechanisms by which microglia detect and respond to their environment are not fully understood, but it is known that microglia express a number of surface receptors and ion channels, including voltage-gated sodium channels, that participate in transduction of external stimuli to intra-cellular responses. To determine whether activated microglia are affected by the activity of sodium channels, we examined the expression of sodium channel isoforms in cultured microglia and the action of sodium channel blockade on multiple functions of activated microglia. Rat microglia in vitro express tetrodotoxin (TTX)-sensitive sodium channels Nav1.1 and Nav1.6 and the TTX-resistant channel Nav1.5, but not detectable levels of Nav1.2, Nav1.3, Nav1.7, Nav1.8, and Nav1.9. Sodium channel blockade with phenytoin (40 microM) and TTX (0.3 microM) significantly reduced by 50-60% the phagocytic activity of microglia activated with lipopolysaccharide (LPS); blockade with 10 microM TTX did not further reduce phagocytic activity. Phenytoin attenuated by approximately 50% the release of IL-1 alpha, IL-1 beta, and TNF-alpha from LPS-stimulated microglia, but had minimal effects on the release of IL-2, IL-4, IL-6, IL-10, MCP-1, and TGF-alpha. TTX (0.3 microM) reduced, but to a smaller extent, the release of IL-1 alpha, IL-1 beta, and TNF-alpha from activated microglia. Phenytoin and TTX also significantly decreased by approximately 50% adenosine triphosphate-induced migration by microglia; studies with microglia cultured from med mice (which lack Nav1.6) indicate that Nav1.6 plays a role in microglial migration. The results demonstrate that the activity of sodium channels contributes to effector roles of activated microglia.
Black
Joel A
JA
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, Connecticut 06518, USA. joel.black@yale.edu
Liu
Shujun
S
Waxman
Stephen G
SG
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D010672:Phenytoin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
D016207:Cytokines; D018836:Inflammation Mediators; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568249:Scn1a protein, mouse; C568250:Scn1a protein, rat; C568321:Scn5a protein, mouse; C568322:Scn5a protein, rat; C507811:Scn8a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D010672:Phenytoin; D000255:Adenosine Triphosphate