Figure 1. Channelopathies can occur as a result of several types of molecular pathology. Genetic channelopathies are the result of mutations in the genes encoding channel proteins. In the autoimmune and toxic channelopathies, the binding of autoantibodies or toxins to channels alters their function. Transcriptional channelopathies are due to dysregulated expression of nonmutated genes which results in the production of an abnormal repertoire of channels whose protein structure is not abnormal.

Figure 2. Spinal sensory neurons and their axons can become hyperexcitable after nerve injury. This intracellular recording shows repetitive action potential activity in a previously transected, regenerating axon from rat sciatic nerve (1 year postcrush) following blockade of potassium channels with 4-aminopyridine. The repetitive impulses arise from a prolonged depolarization that follows the first action potential. This bursting and the slow depolarization are not seen in uninjured axons. (Modified from Kocsis and Waxman (1983).)

Figure 3. Sodium channel gene expression is altered following transection of the axons of dorsal root ganglion (DRG) neurons. SCN10A (Na_v1.8) (top row) and SCN11A (Na_v1.9) (middle row) sodium channel genes turn off, while the SCN3A (Na_v1.3) sodium channel gene turns on in DRG neurons (lower row) following axonal transection within the sciatic nerve. Micrographs (right column) show in situ hybridizations in control DRG and 5–7 days following axotomy. Gels (left) show reverse transcriptase polymerase chain reaction (RT-PCR) products following coamplification of Na_v1.8 (top left) and Na_v1.3 mRNA (bottom left) together with -actin transcripts in control (C) and axotomized DRG (A) (days postaxotomy indicated above gels), with computer-enhanced images of amplification products shown below the gels. Coamplification of Na_v1.9 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (middle row, left) shows decreased expression of Na_v1.9 mRNA at 7 days' postaxotomy (lanes 2, 4, 6) compared with uninjured controls (lanes 1, 3, 5). (Upper and lower panels modified from Dib-Hajj et al. (1996) and middle panels from Dib-Hajj et al. (1998).)

Figure 4. Amplitudes of the currents produced by the SCN10A (Na_v1.8), SCN11A (Na_v1.9) and SCN3A (Na_v1.3) channels are altered following transection of the axons of spinal sensory neurons within the sciatic nerve. (a) Panels 1 and 2 show patch clamp records of currents produced by Na_v1.8 and Na_v1.9 channels in control (uninjured) spinal sensory neurons. (b) Panels 1 and 2 show the currents from similar neurons 7 days after transection of their axons within the sciatic nerve. (Reproduced from Cummins et al. (2000).) (c–e) A rapidly repriming tetrodotoxin-sensitive (TTX-S) current emerges in peripherally axotomized spinal sensory neurons. (c) Family of tetrodotoxin-sensitive sodium current traces (with recovery times indicated) showing the time course of recovery from inactivation (repriming) at –80 mV, from a control spinal sensory neuron. (d) Similar family of traces showing accelerated repriming in a spinal sensory neuron whose axon had been transected 7 days previously. (e) Single exponential fits showing accelerated recovery from inactivation in spinal sensory neurons following axonal transection. (Reproduced from Black et al. (1999a).)

Figure 5. Expression of the sensory neuron-specific (SNS) sodium channel SCN10A (Na_v1.8) is upregulated within cerebellar Purkinje cells in patients with MS. In situ hybridization with Na_v1.8-specific antisense riboprobes demonstrates increased Na_v1.8 mRNA in Purkinje cells from MS patients obtained at post-mortem (a), (b), compared with control without neurological disease (c). No signal is present following hybridization with sense riboprobe (d). Immunocytochemistry with SNS-specific antibodies demonstrates upregulation of Na_v1.8 channel protein in Purkinje cells from MS patients (e, f) compared with controls (g) (arrowhead indicates Purkinje cell). Magnifications: (a) ×120, inset ×280; (b–d) ×165; (e–g) ×175. (Reproduced from Black et al. (2000).)