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The pentapeptide QYNAD does not block voltage-gated sodium channels

From the Department of Neurology (Drs. Cummins, Renganathan, Herzog, Dib-Hajj, and Waxman) and PVA/EPVA Neuroscience Research Center, Yale University School of Medicine, New Haven, and Rehabilitation Research Center (Drs. Cummins, Renganathan, Herzog, Dib-Hajj, and Waxman), VA Medical Center, West Haven, CT; Division of Neuroscience (Dr. Stys), Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario; and Department of Physiology and Institute of Hyperexcitability (K. Scarfo and Dr. Horn), Thomas Jefferson University Medical College, Philadelphia, PA.

Address correspondence and reprint requests to Dr. Stephen G. Waxman, Department of Neurology, LCI 707, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8018; e-mail: stephen.waxman{at}yale.edu

Background: An endogenous pentapeptide (Gln-Tyr-Asn-Ala-Asp; QYNAD) that is present at elevated levels in human CSF from patients with demyelinating diseases has been reported to block voltage-gated sodium channels at low (10 µM) concentrations.

Objective : Because of the potential importance of sodium channel blocking activity in demyelinating disorders, this study attempted to determine the sensitivity to QYNAD of different sodium channel subtypes, including Na_v1.6, the major sodium channel at nodes of Ranvier, and Na_v1.2, which is expressed in axons with abnormal myelin.

Methods: Sodium channel function was assayed using patch-clamp recordings, both in heterologous expression systems and in intact neurons.

Results: QYNAD synthesized in 10 different batches by four different facilities failed to block sodium currents, even at concentrations as high as 500 µM (50-fold higher than the blocking concentration originally reported). QYNAD had no effect on the currents produced by recombinant Na_v1.2, Na_v1.4, Na_v1.6, and Na_v1.7 sodium channels or on the sodium currents that are produced by native channels in adult hippocampal or dorsal root ganglion neurons. QYNAD did not interfere with conduction in the optic nerve, a myelinated fiber tract that is often affected in MS.

Conclusions: These experiments do not show any sodium channel blocking effect of QYNAD. The conclusion that QYNAD contributes to the pathophysiology of inflammatory neurologic disorders by blocking voltage-gated sodium channels should therefore be viewed with caution.

This article has been cited by other articles:

				H. Brinkmeier, F. Weber, P. Aulkemeyer, K. H. Wollinsky, R. Rudel, T. R. Cummins, M. Renganathan, R.I. Herzog, S.D. Dib-Hajj, S.G. Waxman, et al. The pentapeptide QYNAD does not block voltage-gated sodium channels Neurology, June 10, 2003; 60(11): 1871 - 1872. [Full Text] [PDF]

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