The NaV1.8 sodium channel and its gene SCN10A are linked to human diseases including painful neuropathy, multiple sclerosis, and cardiac rhythm disorders, highlighting potential therapeutic targets.
The NaV1.8 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 NaV1.8 demonstrated depolarized voltage dependence of channel inactivation, a slow rate of inactivation, and rapid recovery from inactivation. As a result of these biophysical properties, NaV1.8 supports repetitive firing in response to sustained depolarization. This article reviews recent studies that reveal multiple links of NaV1.8 to human disease: (1) It has recently been shown that functional attributes that distinguish NaV1.8 from other sodium channel subtypes are exaggerated in human NaV1.8; its influence on neuronal activity is thus greater than previously thought. (2) Gain-of-function mutations of NaV1.8 that produce DRG neuron hyperexcitability have been found in 3% of patients with painful neuropathy, establishing a role in pathogenesis. (3) NaV1.8 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 NaV1.8 in neurologic disease may have therapeutic implications. NaV1.8-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 NaV1.8 in human disease raise new questions, but also suggest new therapeutic strategies.
Han et al. (Sat,) conducted a review in Neurologic and cardiac diseases (painful neuropathy, multiple sclerosis, cardiac rhythm disorders). NaV1.8 sodium channel (SCN10A gene) was evaluated. The NaV1.8 sodium channel and its gene SCN10A are linked to human diseases including painful neuropathy, multiple sclerosis, and cardiac rhythm disorders, highlighting potential therapeutic targets.