Regulation of cell surface expression of voltage-dependent Nav1.7 sodium channels:: MRNA stability and posttranscriptional control in adrenal chromaffin cells
Regulation of cell surface expression of voltage-dependent Nav1.7 sodium channels:: MRNA stability and posttranscriptional control in adrenal chromaffin cells
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DOI：
10.2741/1314
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发表时间：
2004-05-01
影响因子：
3.1
通讯作者：
Kobayashi, H
中科院分区：
文献类型：
--
作者：
Wada, A;Yanagita, T;Kobayashi, H
调节表达的Na+通道是必不可少的生理事件，而表达失调，否则沉默，甚至正常的Na+通道亚型导致Na+通道病，然而，监管机制仍然未知。在静止培养的牛肾上腺嗜铬细胞中，细胞外信号调节激酶1（ERK 1）和ERK 2的组成性磷酸化/激活使Na-v 1.7 Na+通道α亚基mRNA不稳定，并降低其水平，而不改变α亚基基因转录，从而负调节稳态水平的Na+通道。蛋白激酶C（PKC）的激活通过PKC亚型特异性机制下调Na+通道;常规PKC-α促进Na+通道的内吞内化，而新型PKC-α使α亚基mRNA不稳定而不改变其基因转录。细胞质Ca 2+的长期（而非短期）增加下调Na+通道; Ca 2+激活的PKC-α和钙蛋白酶的缓慢发展的中度增加，促进Na+通道的内化，而Ca 2+的立即双相和显著的平台期增加降低α和β（1）亚基mRNA水平。钙调磷酸酶，或FK 506结合蛋白和雷帕霉素相关蛋白（FRAP），丝氨酸/苏氨酸蛋白激酶，下调，而胰岛素受体酪氨酸激酶或蛋白激酶A（PKA），通过调节Na+通道内化，和/或Na+通道外化从trans-Golgi网络上调Na+通道。神经保护、抗癫痫、抗精神病和局部麻醉药物通过转录/翻译事件上调Na+通道。
Regulated expression of Na+ channels is indispensable to physiological events, whereas dysregulated expression of otherwise silent or even normal Na+ channel isoforms causes Na+ channelopathies; however, the regulatory mechanisms remain unknown. In quiescent cultured bovine adrenal chromaffin cells, constitutive phosphorylation/activation of extracellular signal-regulated kinase-1 (ERK1) and ERK2 destabilized Na-v 1.7 Na+ channel alpha-subunit mRNA and decreased its level without altering alpha-subunit gene transcription, thus negatively regulating steady-state level of Na+ channels. Activation of protein kinase C (PKC) down-regulated Na+ channels via PKC isoform-specific mechanisms; conventional PKC-alpha promoted endocytic internalization of Na+ channels, whereas novel PKC-epsilon destabilized alpha-subunit mRNA without altering its gene transcription. Long-lasting (but not short-term) increase of cytoplasmic Ca2+ down-regulated Na+ channels; a slowly-developing moderate increase of Ca2+ activated PKC-alpha and calpain, promoting internalization of Na+ channels, whereas an immediate monophasic and salient plateau increase of Ca2+ lowered alpha- and beta(1)-subunit mRNA levels. Calcineurin, or FK506 binding protein-and rapamycin-associated protein (FRAP), a serine/threonine protein kinase, down-regulated, whereas insulin receptor tyrosine kinase or protein kinase A (PKA) up-regulated, Na+ channels via modulating Na+ channel internalization, and/or Na+ channel externalization from the trans-Golgi network. Neuroprotective, antiepiletic, antipsychotic, and local anesthetic drugs up-regulated Na+ channels via transcriptional/translational events.