sodium channel - 0026-895X/08/7405-1476 1484$20.00...

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ProTx-II, a Selective Inhibitor of Na V 1.7 Sodium Channels, Blocks Action Potential Propagation in Nociceptors William A. Schmalhofer, Jeffrey Calhoun, Rachel Burrows, Timothy Bailey, Martin G. Kohler, Adam B. Weinglass, Gregory J. Kaczorowski, Maria L. Garcia, Martin Koltzenburg, and Birgit T. Priest Department of Ion Channels, Merck Research Laboratories, Rahway, New Jersey (W.S., J.C., T.B., M.G.K., A.B.W., G.J.K., M.L.G., B.T.P.); and University College London Institute of Neurology and Department of Clinical Neurophysiology (R.B., M.K.), and University College London Institute of Child Health (M.K.), Queen Square, London, United Kingdom Received March 31, 2008; accepted August 25, 2008 ABSTRACT Voltage-gated sodium (Na V 1) channels play a critical role in modulating the excitability of sensory neurons, and human genetic evidence points to Na V 1.7 as an essential contributor to pain signaling. Human loss-of-function mutations in SCN9A, the gene encoding Na V 1.7, cause channelopathy-associated indifference to pain (CIP), whereas gain-of-function mutations are associated with two inherited painful neuropathies. Al- though the human genetic data make Na V 1.7 an attractive target for the development of analgesics, pharmacological proof-of-concept in experimental pain models requires Na V 1.7- selective channel blockers. Here, we show that the tarantula venom peptide ProTx-II selectively interacts with Na V 1.7 chan- nels, inhibiting Na V 1.7 with an IC 50 value of 0.3 nM, compared with IC 50 values of 30 to 150 nM for other heterologously expressed Na V 1 subtypes. This subtype selectivity was abol- ished by a point mutation in DIIS3. It is interesting that appli- cation of ProTx-II to desheathed cutaneous nerves completely blocked the C-fiber compound action potential at concentra- tions that had little effect on A b -fiber conduction. ProTx-II application had little effect on action potential propagation of the intact nerve, which may explain why ProTx-II was not efficacious in rodent models of acute and inflammatory pain. Mono-iodo-ProTx-II ( 125 I-ProTx-II) binds with high affinity ( K d 5 0.3 nM) to recombinant hNa V 1.7 channels. Binding of 125 I- ProTx-II is insensitive to the presence of other well character- ized Na V 1 channel modulators, suggesting that ProTx-II binds to a novel site, which may be more conducive to conferring subtype selectivity than the site occupied by traditional local anesthetics and anticonvulsants. Thus, the 125 I-ProTx-II bind- ing assay, described here, offers a new tool in the search for novel Na V 1.7-selective blockers. Pain relief remains an important, currently unmet, medi- cal need. Voltage-gated sodium channels play a critical role in modulating the excitability of most neurons, including nociceptive sensory neurons signaling pain. Despite the clin- ical use of systemically administered lidocaine to treat chronic pain since the 1950s (Kugelberg and Lindblom, 1959) and the approval of the weak sodium channel blocker car- bamazepine for the treatment of trigeminal neuralgia (Campbell et al., 1966), several oral sodium channel blockers
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sodium channel - 0026-895X/08/7405-1476 1484$20.00...

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