PMID- 32114117
OWN - NLM
STAT- MEDLINE
DCOM- 20210419
LR  - 20231103
IS  - 1872-7972 (Electronic)
IS  - 0304-3940 (Print)
IS  - 0304-3940 (Linking)
VI  - 724
DP  - 2020 Apr 17
TI  - The voltage-gated sodium channel inhibitor, 4,9-anhydrotetrodotoxin, blocks human 
      Na(v)1.1 in addition to Na(v)1.6.
PG  - 134853
LID - S0304-3940(20)30123-3 [pii]
LID - 10.1016/j.neulet.2020.134853 [doi]
AB  - Voltage-gated sodium channels (VGSCs) are responsible for the initiation and 
      propagation of action potentials in neurons. The human genome includes ten human 
      VGSC alpha-subunit genes, SCN(X)A, encoding Na(v)1.1-1.9 plus Na(x). To understand 
      the unique role that each VGSC plays in normal and pathophysiological function in 
      neural networks, compounds with high affinity and selectivity for specific VGSC 
      subtypes are required. Toward that goal, a structural analog of the VGSC pore 
      blocker tetrodotoxin, 4,9-anhydrotetrodotoxin (4,9-ah-TTX), has been reported to 
      be more selective in blocking Na(+) current mediated by Na(v)1.6 than other 
      TTX-sensitive VGSCs, including Na(v)1.2, Na(v)1.3, Na(v)1.4, and Na(v)1.7. While 
      SCN1A, encoding Na(v)1.1, has been implicated in several neurological diseases, 
      the effects of 4,9-ah-TTX on Na(v)1.1-mediated Na(+) current have not been 
      tested. Here, we compared the binding of 4,9-ah-TTX for human and mouse brain 
      preparations, and the effects of 4,9-ah-TTX on human Na(v)1.1-, Na(v)1.3- and 
      Na(v)1.6-mediated Na(+) currents using the whole-cell patch clamp technique in 
      heterologous cells. We show that, while 4,9-ah-TTX administration results in 
      significant blockade of Na(v)1.6-mediated Na(+) current in the nanomolar range, 
      it also has significant effects on Na(v)1.1-mediated Na(+) current. Thus, 
      4,9-ah-TTX is not a useful tool in identifying Na(v)1.6-specific effects in human 
      brain networks.
CI  - Copyright (c) 2020 Elsevier B.V. All rights reserved.
FAU - Denomme, Nicholas
AU  - Denomme N
AD  - Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, 48109 
      United States; Center for Consciousness Science, University of Michigan, Ann 
      Arbor, Michigan, 48109 United States.
FAU - Lukowski, April L
AU  - Lukowski AL
AD  - Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan, 48109 
      United States; Life Sciences Institute, University of Michigan, Ann Arbor, 
      Michigan, 48109 United States.
FAU - Hull, Jacob M
AU  - Hull JM
AD  - Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, 48109 
      United States.
FAU - Jameson, Margaret B
AU  - Jameson MB
AD  - Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, 48109 
      United States; Molecular and Cellular Pharmacology Training Program, University 
      of Wisconsin School of Medicine and Public Health, Madison, WI 53705 United 
      States.
FAU - Bouza, Alexandra A
AU  - Bouza AA
AD  - Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, 48109 
      United States.
FAU - Narayan, Alison R H
AU  - Narayan ARH
AD  - Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan, 48109 
      United States; Life Sciences Institute, University of Michigan, Ann Arbor, 
      Michigan, 48109 United States; Department of Chemistry, University of Michigan, 
      Ann Arbor, Michigan, 48109 United States.
FAU - Isom, Lori L
AU  - Isom LL
AD  - Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, 48109 
      United States; Department of Molecular and Integrative Physiology, University of 
      Michigan, Ann Arbor, Michigan, 48109 United States; Neuroscience Graduate 
      Program, University of Michigan, Ann Arbor, Michigan, 48109 United States; 
      Department of Neurology, University of Michigan, Ann Arbor, Michigan, 48109 
      United States. Electronic address: lisom@umich.edu.
LA  - eng
GR  - F31 HL144047/HL/NHLBI NIH HHS/United States
GR  - F31 NS111906/NS/NINDS NIH HHS/United States
GR  - R35 GM124880/GM/NIGMS NIH HHS/United States
GR  - R37 NS076752/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20200227
PL  - Ireland
TA  - Neurosci Lett
JT  - Neuroscience letters
JID - 7600130
RN  - 0 (NAV1.1 Voltage-Gated Sodium Channel)
RN  - 0 (NAV1.6 Voltage-Gated Sodium Channel)
RN  - 0 (SCN1A protein, human)
RN  - 0 (SCN8A protein, human)
RN  - 0 (Voltage-Gated Sodium Channel Blockers)
RN  - 13072-89-4 (anhydrotetrodotoxin)
RN  - 4368-28-9 (Tetrodotoxin)
SB  - IM
MH  - Animals
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - HEK293 Cells
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, 129 Strain
MH  - Mice, Transgenic
MH  - NAV1.1 Voltage-Gated Sodium Channel/*physiology
MH  - NAV1.6 Voltage-Gated Sodium Channel/*physiology
MH  - Species Specificity
MH  - Tetrodotoxin/*analogs & derivatives/pharmacology
MH  - Voltage-Gated Sodium Channel Blockers/*pharmacology
PMC - PMC7096269
MID - NIHMS1575399
OTO - NOTNLM
OT  - 4,9-anhydrotetrodotoxin
OT  - Na(v)1.1
OT  - Voltage-gated sodium channels
EDAT- 2020/03/03 06:00
MHDA- 2021/04/20 06:00
PMCR- 2021/04/17
CRDT- 2020/03/02 06:00
PHST- 2019/10/13 00:00 [received]
PHST- 2020/02/12 00:00 [revised]
PHST- 2020/02/18 00:00 [accepted]
PHST- 2020/03/03 06:00 [pubmed]
PHST- 2021/04/20 06:00 [medline]
PHST- 2020/03/02 06:00 [entrez]
PHST- 2021/04/17 00:00 [pmc-release]
AID - S0304-3940(20)30123-3 [pii]
AID - 10.1016/j.neulet.2020.134853 [doi]
PST - ppublish
SO  - Neurosci Lett. 2020 Apr 17;724:134853. doi: 10.1016/j.neulet.2020.134853. Epub 
      2020 Feb 27.