The pentapeptide QYNAD does not block voltage-gated sodium channels.
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 micro M) 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(v)1.6, the major sodium channel at nodes of Ranvier, and Na(v)1.2, 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 micro M (50-fold higher than the blocking concentration originally reported). QYNAD had no effect on the currents produced by recombinant Na(v)1.2, Na(v)1.4, Na(v)1.6, and Na(v)1.7 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.
Cummins
T R
TR
Department of Neurology, PVA/EPVA Neuroscience Research Center, Yale University School of Medicine, New Haven, VA Medical Center, West Haven, CT, USA.
Renganathan
M
M
Stys
P K
PK
Herzog
R I
RI
Scarfo
K
K
Horn
R
R
Dib-Hajj
S D
SD
Waxman
S G
SG
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009900:Optic Nerve / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014981:Xenopus
D009842:Oligopeptides; D011994:Recombinant Proteins; D015222:Sodium Channels; C450845:pentapeptide QYNAD