Search

Provides information on NaN/Na[sub v] 1.9 sodium channel. Effects of sodium channel on electroresponsive properties of primary nociceptive neurons; Role of the channel in nociception; Identification and cloning of the sodium channel; Physiological significance of sodium channel.

Investigates the role of voltage-gated sodium (Na+) channels in glia. Involvement of Schwann cells and astrocytes; Similarities and differences between glial and neuronal Na+ channels; Reasons for glial cell inexcitability; Functions of the glial Na+ channels.

Gain-of-function mutations or dysregulated expression of voltage-gated sodium channels can produce neuronal hyperexcitability, leading to acute or chronic pain. The sodium channel Nav1.7 is expressed preferentially in most slowly conducting nociceptive neurons and in sympathetic neurons. Gain-of-function mutations in the Nav1.7 channel lead to DRG neuron hyperexcitability associated with severe pain, whereas loss of the Nav1.7 channel in patients leads to indifference to pain. The contribution of Nav1.7 to acquired and inherited pain states and the absence of motor, cognitive and cardiac deficits in patients lacking this channel make it an attractive target for the treatment of neuropathic pain. [Copyright &y& Elsevier]

Following the loss of myelin from axons in multiple sclerosis, some axons recover the ability to conduct impulses despite the absence of an insulating sheath, providing a basis for remission of clinical deficits. By contrast, other axons degenerate and contribute to non-remitting clinical deficits and, thus, disability. Investigations using laboratory models of multiple sclerosis indicate that altered expression of two distinct isoforms of Na+ channels underlies these two processes, and the study of human tissue reveals similar changes in multiple sclerosis. [Copyright &y& Elsevier]

Recent studies have indicated that, in addition to demyelination and axonal degeneration, a third factor, dysregulated ion channel expression, contributes to the pathophysiology of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). Consistent with this suggestion, upregulated expression of sodium channel Nav1.8 is observed in Purkinje neurons in EAE and MS, and biophysical studies indicate that aberrant expression of Nav1.8 produces abnormal Purkinje cell firing which may contribute to the development of cerebellar ataxia. However, the molecular mechanisms that contribute to the upregulation of Nav1.8 in Purkinje cells in EAE and MS have not yet been determined. Previous studies have shown that neurotrophic factors can modulate sodium channel expression and that elevated levels of NGF are present in EAE and MS. Using immunocytochemical methods, we examined the relationship between the upregulation of Nav1.8 and the expression of the NGF receptors p75 and TrkA in EAE. Here we demonstrate that upregulation of Nav1.8 is associated with expression of p75 and low levels of TrkA in the majority of Purkinje cells in EAE. These findings, together with previous studies demonstrating a modulatory role of NGF on sodium channel expression, suggest that NGF acting via p75 contributes to the upregulation of Nav1.8 in Purkinje cells in EAE. [Copyright &y& Elsevier]

Peripheral neuropathy results from damage to peripheral nerves and is often accompanied by pain in affected limbs. Treatment represents an unmet medical need and a thorough understanding of the mechanisms underlying axonal injury is needed. Longer nerve fibers tend to degenerate first (length-dependence), and patients carrying pathogenic mutations throughout life usually become symptomatic in mid- or late-life (time-dependence). The activity of voltage-gated sodium channels can contribute to axonal injury and sodium channel gain-of-function mutations have been linked to peripheral neuropathy. Recent studies have implicated sodium channel activity, mitochondrial compromise, and reverse-mode Na + /Ca 2+ exchange in time- and length-dependent axonal injury. Elucidation of molecular mechanisms underlying axonal injury in peripheral neuropathy may provide new therapeutic strategies for this painful and debilitating condition. [ABSTRACT FROM AUTHOR]