Voltage-dependent Na+ channel: quality control and stress response.

在电压依赖性Na^+通道的9种亚型中，Na_v1.7作为第一个有说服力的镇痛药物分子靶点而受到广泛关注。Na_v1.7的异常上调或Na_v1.7或交感神经系统的过度兴奋导致慢性不可耐受的疼痛（例如疼痛性糖尿病神经病变和炎性疼痛）。在培养的牛肾上腺嗜铬细胞中，我们研究了各种信号分子调节细胞表面Na_v1.7表达的机制，以及Na_v1.7调节的细胞后果。细胞质：Ca^<2+>超载激活蛋白激酶C-α和钙蛋白酶，降低细胞表面Na_v1.7。持续的高度Ca^<2+>超载降低Na^+通道α和β_1亚基mRNA水平，而持续的（但不是短暂的）中度Ca^<2+>超载足以促进细胞表面Na_v1.7.2的内吞内化。胰岛素和胰岛素样生长因子-I（IGF-I），两种生长因子促进胰岛素分泌， 关于我们 ng神经发生和神经保护/神经再生，通过差异机制增加细胞表面Na_v1.7。IGF-I抑制糖原合成酶激酶-3 β（GSK-3β），增加Na_v1.7基因的转录和细胞表面表达，<22>通过上调Na_v1.7增加Na^+内流<45>，增加电压依赖性Ca^2+通道的Ca^2+内流和细胞外分泌儿茶酚胺。锂是一种治疗急性神经元损伤和慢性神经退行性疾病的药物，其作用与IGF-I相似。溶血磷脂酸（LPA）是一种引起神经源性疼痛的脂质信号，它激活LPA_1受体，增加Na^+通道α和β_1亚基mRNA水平，上调细胞表面Na ^+1.7和<22>Na^+内流。上调的Na^+通道的电生理特性与天然Na_v 1.7.4相当。胰岛素缺乏诱导的糖尿病神经病变影响运动、感觉和自主神经元，归因于Na^+通道表达和定位失调。抗胰岛素抵抗药物曲格列酮降低了Na_v1.7的细胞表面数量。少

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 … More 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