期刊
NEUROLOGY
卷 86, 期 5, 页码 473-483出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0000000000002333
关键词
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资金
- Department of Veterans Affairs
- Paralyzed Veterans of America
- Erythromelalgia Association
- Pfizer Research
- Convergence Pharmaceuticals
The Na(V)1.8 sodium channel, encoded by gene SCN10A, was initially termed sensory neuron-specific (SNS) due to prominent expression in primary sensory neurons including dorsal root ganglion (DRG) neurons. Early studies on rodent Na(V)1.8 demonstrated depolarized voltage dependence of channel inactivation, a slow rate of inactivation, and rapid recovery from inactivation. As a result of these biophysical properties, Na(V)1.8 supports repetitive firing in response to sustained depolarization. This article reviews recent studies that reveal multiple links of Na(V)1.8 to human disease: (1) It has recently been shown that functional attributes that distinguish Na(V)1.8 from other sodium channel subtypes are exaggerated in human Na(V)1.8; its influence on neuronal activity is thus greater than previously thought. (2) Gain-of-function mutations of Na(V)1.8 that produce DRG neuron hyperexcitability have been found in 3% of patients with painful neuropathy, establishing a role in pathogenesis. (3) Na(V)1.8 is ectopically expressed within Purkinje neurons in multiple sclerosis (MS), where it perturbs electrical activity. Recent evidence indicates that variants of SCN10A predict the degree of cerebellar dysfunction in MS. (4) Emerging evidence has linked SCN10A variants to disorders of cardiac rhythm, via mechanisms that may include an effect on cardiac innervation. Involvement of Na(V)1.8 in neurologic disease may have therapeutic implications. Na(V)1.8-specific blocking agents, under development, ameliorate pain and attenuate MS-like deficits in animal models. Recent studies suggest that pharmacogenomics may permit the matching of specific channel blocking agents to particular patients. The new links of Na(V)1.8 in human disease raise new questions, but also suggest new therapeutic strategies.
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