PMID- 26859646
OWN - NLM
STAT- MEDLINE
DCOM- 20160829
LR  - 20220316
IS  - 1528-1175 (Electronic)
IS  - 0003-3022 (Linking)
VI  - 124
IP  - 5
DP  - 2016 May
TI  - Quaternary Lidocaine Derivative QX-314 Activates and Permeates Human TRPV1 and 
      TRPA1 to Produce Inhibition of Sodium Channels and Cytotoxicity.
PG  - 1153-65
LID - 10.1097/ALN.0000000000001050 [doi]
AB  - BACKGROUND: The relatively membrane-impermeable lidocaine derivative QX-314 has 
      been reported to permeate the ion channels transient receptor potential vanilloid 
      1 (TRPV1) and transient receptor potential cation channel, subfamily A, member 1 
      (TRPA1) to induce a selective inhibition of sensory neurons. This approach is 
      effective in rodents, but it also seems to be associated with neurotoxicity. The 
      authors examined whether the human isoforms of TRPV1 and TRPA1 allow 
      intracellular entry of QX-314 to mediate sodium channel inhibition and 
      cytotoxicity. METHODS: Human embryonic kidney 293 (HEK-293) cells expressing 
      wild-type or mutant human (h) TRPV1 or TRPA1 constructs as well as the sodium 
      channel Nav1.7 were investigated by means of patch clamp and ratiometric calcium 
      imaging. Cytotoxicity was examined by flow cytometry. RESULTS: Activation of 
      hTRPA1 by carvacrol and hTRPV1 by capsaicin produced a QX-314-independent 
      reduction of sodium current amplitudes. However, permeation of QX-314 through 
      hTRPV1 or hTRPA1 was evident by a concentration-dependent, use-dependent 
      inhibition of Nav1.7 activated at 10 Hz. Five and 30 mM QX-314 activated hTRPV1 
      via mechanisms involving the intracellular vanilloid-binding domain and hTRPA1 
      via unknown mechanisms independent of intracellular cysteins. Expression of 
      hTRPV1, but not hTRPA1, was associated with a QX-314-induced cytotoxicity (viable 
      cells 48 +/- 5% after 30 mM QX-314) that was ameliorated by the TRPV1 antagonist 
      4-(3-chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide 
      (viable cells 81 +/- 5%). CONCLUSIONS: The study data demonstrate that QX-314 
      directly activates and permeates the human isoforms of TRPV1 and TRPA1 to induce 
      inhibition of sodium channels, but also a TRPV1-dependent cytotoxicity. These 
      results warrant further validation of this approach in more intact preparations 
      and may be valuable for the development of this concept into clinical practice.
FAU - Stueber, Thomas
AU  - Stueber T
AD  - From the Department of Anaesthesiology and Intensive Care Medicine, Hannover 
      Medical School, Hannover, Germany (T.S., M.J.E., C.H., A.J., S.S., F.D., C.S., 
      A.L.); Department of Physiology and Pathophysiology, 
      Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany (K.K., 
      P.W.R.); and Department of Medical Neurobiology, Institute for Medical Research 
      Israel-Canada, The Hebrew University Faculty of Medicine, and The Edmond and Lily 
      Safra Center for Brain Sciences, The Hebrew University, Jerusalem, Israel 
      (A.M.B.).
FAU - Eberhardt, Mirjam J
AU  - Eberhardt MJ
FAU - Hadamitzky, Christoph
AU  - Hadamitzky C
FAU - Jangra, Annette
AU  - Jangra A
FAU - Schenk, Stefan
AU  - Schenk S
FAU - Dick, Felicia
AU  - Dick F
FAU - Stoetzer, Carsten
AU  - Stoetzer C
FAU - Kistner, Katrin
AU  - Kistner K
FAU - Reeh, Peter W
AU  - Reeh PW
FAU - Binshtok, Alexander M
AU  - Binshtok AM
FAU - Leffler, Andreas
AU  - Leffler A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Anesthesiology
JT  - Anesthesiology
JID - 1300217
RN  - 0 (Anesthetics, Local)
RN  - 0 (Calcium Channels)
RN  - 0 (NAV1.7 Voltage-Gated Sodium Channel)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (SCN9A protein, human)
RN  - 0 (Sodium Channel Blockers)
RN  - 0 (TRPA1 Cation Channel)
RN  - 0 (TRPA1 protein, human)
RN  - 0 (TRPV Cation Channels)
RN  - 0 (TRPV1 protein, human)
RN  - 0 (Transient Receptor Potential Channels)
RN  - 21306-56-9 (QX-314)
RN  - 98PI200987 (Lidocaine)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Anesthetics, Local/*pharmacology
MH  - Calcium/metabolism
MH  - Calcium Channels/*drug effects
MH  - Cell Survival/*drug effects
MH  - Dose-Response Relationship, Drug
MH  - HEK293 Cells
MH  - Humans
MH  - Lidocaine/*analogs & derivatives/pharmacology
MH  - NAV1.7 Voltage-Gated Sodium Channel/drug effects
MH  - Nerve Tissue Proteins/agonists/*drug effects
MH  - Sodium Channel Blockers/*pharmacology
MH  - TRPA1 Cation Channel
MH  - TRPV Cation Channels/agonists/*drug effects
MH  - Transient Receptor Potential Channels/agonists/*drug effects
EDAT- 2016/02/10 06:00
MHDA- 2016/08/30 06:00
CRDT- 2016/02/10 06:00
PHST- 2016/02/10 06:00 [entrez]
PHST- 2016/02/10 06:00 [pubmed]
PHST- 2016/08/30 06:00 [medline]
AID - 10.1097/ALN.0000000000001050 [doi]
PST - ppublish
SO  - Anesthesiology. 2016 May;124(5):1153-65. doi: 10.1097/ALN.0000000000001050.