title: N-type calcium channel in the pathogenesis of experimental autoimmune encephalomyelitis.
abstract: One of the family of voltage-gated calcium channels (VGCC), the N-type Ca(2+) channel, is located predominantly in neurons and is associated with a variety of neuronal responses, including neurodegeneration. A precise mechanism for how the N-type Ca(2+) channel plays a role in neurodegenerative disease, however, is unknown. In this study, we immunized N-type Ca(2+) channel α(1B)-deficient (α(1B)(-/-)) mice and their wild type (WT) littermates with myelin oligodendrocyte glycoprotein 35-55 and analyzed the progression of experimental autoimmune encephalomyelitis (EAE). The neurological symptoms of EAE in the α(1B)(-/-) mice were less severe than in the WT mice. In conjunction with these results, sections of the spinal cord (SC) from α(1B)(-/-) mice revealed a reduction in both leukocytic infiltration and demyelination compared with WT mice. No differences were observed in the delayed-type hypersensitivity response, spleen cell proliferation, or cytokine production from splenocytes between the two genotypes. On the other hand, Western blot array analysis and RT-PCR revealed that a typical increase in the expression of MCP-1 in the SC showed a good correlation with the infiltration of leukocytes into the SC. Likewise, immunohistochemical analysis showed that the predominant source of MCP-1 was activated microglia. The cytokine-induced production of MCP-1 in primary cultured microglia from WT mice was significantly higher than that from α(1B)(-/-) mice and was significantly inhibited by a selective N-type Ca(2+) channel antagonist, ω-conotoxin GVIA or a withdrawal of extracellular Ca(2+). These results suggest that the N-type Ca(2+) channel is involved in the pathogenesis of EAE at least in part by regulating MCP-1 production by microglia.
authors: From the Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Chiba 260-8670; Department of Biology/Pharmacology, Discovery Research, Neuroscience Product Creation Unit, Tsukuba, Ibaraki 300-2635, Japan.
authors: Naoki
authors: N
authors: Tokuhara
authors: From the Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Chiba 260-8670.
authors: Kana
authors: K
authors: Namiki
authors: Department of Genomics, Biomarkers and Personalized Medicine Core Function Unit, Tsukuba, Ibaraki 300-2635, Japan.
authors: Mai
authors: M
authors: Uesugi
authors: Department of Tsukuba Discovery Research, KAN Product Creation Unit, Tsukuba, Ibaraki 300-2635, Japan.
authors: Chihiro
authors: C
authors: Miyamoto
authors: Department of Biology/Pharmacology, Discovery Research, Neuroscience Product Creation Unit, Tsukuba, Ibaraki 300-2635, Japan.
authors: Makoto
authors: M
authors: Ohgoh
authors: Department of Biology/Pharmacology, Discovery Research, Neuroscience Product Creation Unit, Tsukuba, Ibaraki 300-2635, Japan.
authors: Katsutoshi
authors: K
authors: Ido
authors: Department of Global Drug Safety, Biopharmaceutical Assessment Core Function Unit, Eisai Company, Limited, Tsukuba, Ibaraki 300-2635, Japan.
authors: Takashi
authors: T
authors: Yoshinaga
authors: Department of Biology/Pharmacology, Discovery Research, Neuroscience Product Creation Unit, Tsukuba, Ibaraki 300-2635, Japan.
authors: Toshihiko
authors: T
authors: Yamauchi
authors: Department of Tsukuba Discovery Research, KAN Product Creation Unit, Tsukuba, Ibaraki 300-2635, Japan.
authors: Junro
authors: J
authors: Kuromitsu
authors: From the Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Chiba 260-8670.
authors: Sadao
authors: S
authors: Kimura
authors: Department of Tsukuba Discovery Research, KAN Product Creation Unit, Tsukuba, Ibaraki 300-2635, Japan.
authors: Norimasa
authors: N
authors: Miyamoto
authors: From the Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Chiba 260-8670. Electronic address: kasuya@faculty.chiba-u.jp.
authors: Yoshitoshi
authors: Y
authors: Kasuya
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D020866:omega-Conotoxin GVIA; D002118:Calcium