Transcriptional channelopathies: An emerging class of disorders

In addition to genetic and autoimmune channelopathies, the two best-known types of this family of disorders, a new class has recently been recognized: transcriptional channelopathies, which are due to the dysregulated transcription of genes that encode normal channel proteins. Transcription of sodium channel genes is a highly dynamic process; it is regulated throughout development, and it can be affected by the availability of neurotrophic factors. In addition, sodium channel transcription can change in response to physiological states such as changes in osmolarity. Sodium channel transcription can also change in response to pathological states. Peripheral nerve injury provides a clear example. In a model of experimental nerve injury, reductions in the expression of some previously active sodium channel genes have been found. Similarly, another sodium channel gene that is normally silent in spinal sensory neurons is induced by nerve injury. These changes are thought to lead to hyperexcitability, and might contribute to the hyperalgesia and allodynia that are observed in cases of neuropathic pain. Some of the signs that accompany multiple sclerosis, such as cerebellar ataxia, could be considered as transcriptional channelopathies. Although increased expression of sodium channels in multiple sclerosis seems to be a compensatory reaction to allow normal action potential conduction in demyelinated nerves, their anomalous expression in Purkinje cells might be responsible for some of the motor abnormalities seen in these patients. There is evidence to suggest that the expression of potassium and calcium channels might also change in certain demyelinating conditions. In addition, other disorders, such as epilepsy, might also be accompanied by alterations in channel expression, raising the possibility that transcriptional channelopathies are a more widespread class of disorders than is appreciated at present.