| Project/Area Number |
16300119
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | University of Miyazaki |
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Principal Investigator |
WADA Akihiko University of Miyazaki, Department of Pharmacology, Professor, 医学部, 教授 (30131949)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Hideyuki University of Miyazaki, Department of Pharmacology, Associate Professor, 医学部, 助教授 (40148953)
YANAGITA Toshihiko University of Miyazaki, Department of Pharmacology, Assistant Professor, 医学部, 助手 (60295227)
YOKOO Hiroki University of Miyazaki, Department of Pharmacology, Assistant Professor, 医学部, 助手 (30332894)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 2006: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2005: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2004: ¥4,100,000 (Direct Cost: ¥4,100,000)
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| Keywords | Nav1.7 Na+ channel / cell surface expression / Ca2+ overload / insulin / insulin-like growth factor / lithium / lysosphosphatidic acid / troglitazone / Na^+チャネル / 翻訳後修飾 / 糖鎖付加 / heat shock protein 90 / glycogen synthase kinase-3β / lysophosphatidic acid / lithium / Hsp90 / 細胞膜発現調節 / IGF-I / GSK-3β / β-アミロイド / インターナリゼーション / 副腎髄質クロマフィン細胞 / 電位依存性Na+チャネル / 血清除去 / β-アミロイド・ペプタイド / プリオン・ペプタイド / glycogen synthase kinase-3 |
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| Research Abstract |
Among nine isoforms of voltage-dependent Na^+ channel, Na_v1.7 has received widespread attention largely as the first convincing molecular target of therapeutic drugs against pain. Abnormal up-regulation of Na_v1.7, or hyperexcitability of Na_v1.7 or sympathetic nervous system causes chronic intolerable pain (e.g. painful diabetic neuropathy and inflammatory pain). In cultured bovine adrenal chromaffin cells, we examined the mechanisms whereby various signaling molecules regulate cell surface expression of Na_v1.7, with cellular consequence of Na_v1.7 regulation.
1. Cytoplasmic : Ca^<2+> overload activated protein kinase C-α and calpain, decreasing cell surface Na_v1.7. Persistent high-degree of Ca^<2+> overload lowered Na^+ channel α-and β_1-subunit mRNA levels, while sustained (but not transient) moderate-degree of Ca^<2+> overload was sufficient to promote endocytic internalization of cell surface Na_v1.7.
2. Insulin and insulin-like growth factor-I (IGF-I), two growth factors promoti
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ng neurogenesis and neuroprotection/neuroregeneration, increased cell surface Na_v1.7 via differential mechanisms. IGF-I inhibited glycogen synthase kinase-3β (GSK-3β), increasing Na_v1.7 gene transcription and its cell surface expression; increased ^<22>Na^+ influx via up-regulate i Na_v1.7 enhanced ^<45>Ca^<2+> influx via voltage-dependent Ca^<2+> channel and exocytic secretion of catecholamines. Lithium, a therapeutics against acute neuronal injuries and chronic neurodegenerative diseases, exhibited effects similar to those of IGF-I.
3. Lysophosphatidic acid (LPA), a lipid signal causing neurogenic pain, activated LPA_1 receptor, and increased Na^+ channel α-and β_1-subunit mRNA levels, up-regulating cell surface Na_v1.7 and ^<22>Na^+ influx. Electrophysiological properties of up-regulated Na^+ channels are comparable with those of native Na_v1.7.
4. Insulin deficiency-induced diabetic neuropathy affects motor, sensory, and autonomic neurons, being attributed to dysregulated expression and localization of Na^+ channels. Troglitazone, a drug against insulin resistance, lowered cell surface number of Na_v1.7. Less
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