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Painful Channels

2006; Cell Press; Volume: 52; Issue: 5 Linguagem: Inglês

10.1016/j.neuron.2006.11.017

1097-4199

William A. Catterall, Frank H. Yu,

Cardiac electrophysiology and arrhythmias

Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, OMIM 167400), is an inherited disease causing intense burning rectal, ocular, and submandibular pain and flushing. Fertleman et al. (this issue of Neuron) show that mutations in SCN9A, the gene encoding the sodium channel NaV1.7 channels, are responsible for this syndrome. Together with earlier work implicating a distinct class of functional mutations in SCN9A in a distinct inherited pain syndrome, these results point to NaV1.7 channels as key players in signaling nociceptive information and as a potential target for drug therapy of chronic pain. Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, OMIM 167400), is an inherited disease causing intense burning rectal, ocular, and submandibular pain and flushing. Fertleman et al. (this issue of Neuron) show that mutations in SCN9A, the gene encoding the sodium channel NaV1.7 channels, are responsible for this syndrome. Together with earlier work implicating a distinct class of functional mutations in SCN9A in a distinct inherited pain syndrome, these results point to NaV1.7 channels as key players in signaling nociceptive information and as a potential target for drug therapy of chronic pain. Besides inheriting annoying relatives, how could one be afflicted with inherited pain in the rectum? In this issue of Neuron, Fertleman et al., 2006Fertleman C.R. Baker M.D. Parker K.A. Moffatt S. Elmslie F.V. Abrahamsen B. Ostman J. Klugbauer N. Wood J.N. Gardiner R.M. Rees M. Neuron. 2006; 52 (this issue): 767-774Abstract Full Text Full Text PDF PubMed Scopus (531) Google Scholar show that paroxysmal extreme pain disorder (PEPD) is caused by mutations in sodium channels that are responsible for action potential conduction in peripheral nerves. Thus, PEPD takes a new place among the ion channelopathies. Ion channelopathies are usually the result of dominant mutations that cause gain-of-function effects leading to hyperactivity of ion channels (Ashcroft, 2000Ashcroft F.M. Ion Channels and Disease. Academic Press, San Diego, CA2000Google Scholar). The first ion channelopathy to be described was hyperkalemic periodic paralysis of skeletal muscle, which is caused by mutations in the skeletal muscle sodium channel NaV1.4 (Venance et al., 2006Venance S.L. Cannon S.C. Fialho D. Fontaine B. Hanna M.G. Ptacek L. Tristani-Firouzi M. Tawil R. Griggs R.C. CINCH investigatorsBrain. 2006; 129: 8-17Crossref PubMed Scopus (224) Google Scholar). Subsequent work has shown that hypokalemic periodic paralysis and paramyotonia congenita of skeletal muscle are also caused by mutations in NaV1.4 channels. Moreover, cardiac arrhythmias in long-QT syndrome type 3 and Brugada syndrome are caused by mutations in NaV1.5 channels expressed in the heart (Keating and Sanguinetti, 2001Keating M.T. Sanguinetti M.C. Cell. 2001; 104: 569-580Abstract Full Text Full Text PDF PubMed Scopus (830) Google Scholar), and generalized epilepsy with febrile seizures plus, benign familial neonatal-infantile convulsions, severe myoclonic epilepsy in infancy, and one form of familial hemiplegic migraine are all caused by mutations in NaV1.1 or NaV1.2 channels in central neurons (Meisler and Kearney, 2005Meisler M.H. Kearney J.A. J. Clin. Invest. 2005; 115: 2010-2017Crossref PubMed Scopus (372) Google Scholar). Although sodium channels transmit pain signals from peripheral nociceptive nerve endings back to the dorsal root ganglion neurons and the spinal cord, the recognition of involvement of these channels in inherited pain syndromes is quite recent. Primary erythermalgia (PE) an inherited syndrome of burning pain and flushing in the extremities, is caused by mutations in the NaV1.7 channel (Yang et al., 2004Yang Y. Wang Y. Li S. Xu Z. Li H. Ma L. Fan J. Bu D. Liu B. Fan Z. et al.J. Med. Genet. 2004; 41: 171-174Crossref PubMed Scopus (558) Google Scholar, Waxman and Dib-Hajj, 2005Waxman S.G. Dib-Hajj S. Trends Mol. Med. 2005; 11: 555-562Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar), which is expressed primarily in peripheral neurons and their axons. These mutations enhance the activation of sodium channels. In contrast, the mutations that cause PEPD impair inactivation of NaV1.7 channels (Fertleman et al., 2006Fertleman C.R. Baker M.D. Parker K.A. Moffatt S. Elmslie F.V. Abrahamsen B. Ostman J. Klugbauer N. Wood J.N. Gardiner R.M. Rees M. Neuron. 2006; 52 (this issue): 767-774Abstract Full Text Full Text PDF PubMed Scopus (531) Google Scholar). Thus, there is a well-defined genotype/phenotype correlation between these two distinct peripheral pain syndromes. Mutations that cause ion channelopathies are scattered widely through the sodium channel structure (Figure 1), but there is a concentration of mutations in regions involved in activation and inactivation gating. Activation of sodium channels and other voltage-gated ion channels is initiated by a voltage-driven conformational change in the voltage sensor domain composed of the S1–S4 segments and their connecting loops in each of the four homologous repeat domains (Figure 1; Catterall, 2000Catterall W.A. Neuron. 2000; 26: 13-25Abstract Full Text Full Text PDF PubMed Scopus (1609) Google Scholar). Depolarization exerts a force on the positively charged arginine or lysine residues in the S4 segment (Figure 1, green), which serve as gating charges. This force leads to outward and rotational motion of the S4 segment and coordinated movement of the S1, S2, and S3 segments around S4 (Tombola et al., 2006Tombola F. Pathak M.M. Isacoff E.Y. Annu. Rev. Cell Dev. Biol. 2006; 22: 23-52Crossref PubMed Scopus (232) Google Scholar, Yarov-Yarovoy et al., 2006Yarov-Yarovoy V. Baker D. Catterall W.A. Proc. Natl. Acad. Sci. USA. 2006; 103: 7292-7297Crossref PubMed Scopus (189) Google Scholar). These structural changes cause opening of the transmembrane pore by pulling on the pore-forming S5 and S6 segments (Figure 1, red) and causing them to bend at a hinge glycine residue. Following activation, the inactivation gate formed by the intracellular loop-connecting domains III and IV (Figure 1) folds into the intracellular mouth of the pore and prevents further sodium conductance (Catterall, 2000Catterall W.A. Neuron. 2000; 26: 13-25Abstract Full Text Full Text PDF PubMed Scopus (1609) Google Scholar). The closed inactivation gate interacts with the S4–S5 loops in domains III and IV and the end of the S6 segment in domain IV on the intracellular surface of the sodium channel (Catterall, 2000Catterall W.A. Neuron. 2000; 26: 13-25Abstract Full Text Full Text PDF PubMed Scopus (1609) Google Scholar). As illustrated by the symbols in Figure 1A (red circles), mutations that cause paramyotonia congenita and related myotonias are primarily located in the inactivation gate loop connecting homologous domains III and IV, the inactivation gate receptor regions in the S4–S5 intracellular loops within domains III and IV and the C-terminal end of the IVS6 segment, and the S4 segment in domain IV that couples activation to inactivation. Failure of inactivation in paramyotonia congenita mutants causes repetitive reopening of these channels and generates the repetitive action potentials that cause the disease. Mutations in these regions are also observed in NaV1.5 channels in inherited cardiac arrhythmias (Figure 1B) and in NaV1.1 channels in generalized epilepsy with febrile seizures plus (Figure 1C). This concentration of mutations in regions that can directly impair the inactivation process is consistent with the conclusion that hyperactivity of sodium channels is most easily generated by block of inactivation. This preferential involvement of mutations that impair inactivation is particularly clear in the case of PEPD (Fertleman et al., 2006Fertleman C.R. Baker M.D. Parker K.A. Moffatt S. Elmslie F.V. Abrahamsen B. Ostman J. Klugbauer N. Wood J.N. Gardiner R.M. Rees M. Neuron. 2006; 52 (this issue): 767-774Abstract Full Text Full Text PDF PubMed Scopus (531) Google Scholar). Of the eight mutations that cause PEPD, three are located in the inactivation gate itself, three in the S4–S5 loop in domain III, and one in the S4–S5 loop in domain IV (Figure 1D, yellow circles). These disease mutations map almost exactly onto the structure-function results for sodium channel inactivation (Catterall, 2000Catterall W.A. Neuron. 2000; 26: 13-25Abstract Full Text Full Text PDF PubMed Scopus (1609) Google Scholar). All of these mutations cause noninactivating sodium currents in NaV1.7 channels, which likely cause the PEPD syndrome by inducing repetitive firing in peripheral nerves that conduct pain information. In contrast, the locations of the mutations that cause PE reveal no overlap with those that cause PEPD. The erythermalgia mutations are located in regions of the sodium channel involved in activation and have specific effects on activation and deactivation gating (Waxman and Dib-Hajj, 2005Waxman S.G. Dib-Hajj S. Trends Mol. Med. 2005; 11: 555-562Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). These results demonstrate a clear molecular basis for the genotype/phenotype correlation between mutations in NaV1.7 channels and the different effects they cause in PEPD and PE. The essential role of NaV1.7 channels in pain, as demonstrated by the mutations in PE and PEPD, points to these channels as an ideal drug target for treatment of chronic pain. Although acute pain is well treated by local application of local anesthetics or by systemic treatment with nonsteroidal anti-inflammatory drugs or opiate drugs, these approaches are not successful for intense chronic pain. Local anesthetics cannot be applied repeatedly to the source of chronic pain in most cases, anti-inflammatory drugs are usually not sufficient to block intense chronic pain, and repeated use of opiates leads to tolerance and addiction. Effective treatment of chronic pain is therefore an important unmet medical need. A recent symposium at the National Medicinal Chemistry Meeting in Seattle, Washington, USA (June, 2006; http://wiz2.pharm.wayne.edu/nmcs30abstracts2006.pdf, pp. 33–36) revealed much progress toward development of novel, high-affinity sodium channel blockers that may be useful for treatment of this difficult condition. Hopefully, we can look forward to new therapeutic agents that will be helpful to patients with PEPD, PE, and the much more common chronic and neuropathic pain from traumatic injury, degenerative spine syndromes, and medical conditions such as arthritis, diabetes, cancer, Herpes infection, and many others. SCN9A Mutations in Paroxysmal Extreme Pain Disorder: Allelic Variants Underlie Distinct Channel Defects and PhenotypesFertleman et al.NeuronDecember 07, 2006In BriefParoxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, or OMIM 167400), is an inherited condition characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. A genome-wide linkage search followed by mutational analysis of the candidate gene SCN9A, which encodes hNav1.7, identified eight missense mutations in 11 families and 2 sporadic cases. Functional analysis in vitro of three of these mutant Nav1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. Full-Text PDF Open Archive