Abstract
Voltage-gated sodium channels are blocked by local anesthetic and anticonvulsant drugs. A receptor site for local anesthetics has been defined in transmembrane segment S6 in domain IV (IVS6) of the α subunit, but the anticonvulsant lamotrigine and related compounds have more complex structures than local anesthetics and may interact with additional amino acid residues. Apparent KD values for inactivated-state block of rat brain type IIA sodium channels expressed in Xenopus oocytes were 31.9 μM, 17.3 μM, 3.7 μM and 10.3 μM for lamotrigine and compounds 227c89, 4030w92 and 619c89, respectively. Compound 619c89 was the strongest frequency-dependent blocker, which correlated with higher affinity and a five-fold slower recovery from drug block compared to lamotrigine. Examination of lamotrigine block of mutant sodium channel α subunits, in which alanine had been substituted for each individual amino acid in IVS6, identified mutations I1760A, F1764A and Y1771A as causing the largest reductions in affinity (six-, seven- and 12-fold, respectively). The ratios of effects of these three mutations differed for compounds 227c89, 4030w92, and 619c89. The amino acid residues interacting with these pore-blocking drugs define a surface of IVS6 that is exposed to the pore and may rotate during gating.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 413-422 |
| Number of pages | 10 |
| Journal | Neuropharmacology |
| Volume | 44 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2003 |
| Externally published | Yes |
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Keywords
- Analgesic
- Anticonvulsant
- Brain
- Ion channel blocker
- Sodium channels
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Drug Discovery
- Pharmacology
Cite this
Differential interactions of lamotrigine and related drugs with transmembrane segment IVS6 of voltage-gated sodium channels. / Liu, G.; Yarov-Yarovoy, Vladimir; Nobbs, M.; Clare, J. J.; Scheuer, T.; Catterall, W. A.
In: Neuropharmacology, Vol. 44, No. 3, 03.2003, p. 413-422.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Differential interactions of lamotrigine and related drugs with transmembrane segment IVS6 of voltage-gated sodium channels
AU - Liu, G.
AU - Yarov-Yarovoy, Vladimir
AU - Nobbs, M.
AU - Clare, J. J.
AU - Scheuer, T.
AU - Catterall, W. A.
PY - 2003/3
Y1 - 2003/3
N2 - Voltage-gated sodium channels are blocked by local anesthetic and anticonvulsant drugs. A receptor site for local anesthetics has been defined in transmembrane segment S6 in domain IV (IVS6) of the α subunit, but the anticonvulsant lamotrigine and related compounds have more complex structures than local anesthetics and may interact with additional amino acid residues. Apparent KD values for inactivated-state block of rat brain type IIA sodium channels expressed in Xenopus oocytes were 31.9 μM, 17.3 μM, 3.7 μM and 10.3 μM for lamotrigine and compounds 227c89, 4030w92 and 619c89, respectively. Compound 619c89 was the strongest frequency-dependent blocker, which correlated with higher affinity and a five-fold slower recovery from drug block compared to lamotrigine. Examination of lamotrigine block of mutant sodium channel α subunits, in which alanine had been substituted for each individual amino acid in IVS6, identified mutations I1760A, F1764A and Y1771A as causing the largest reductions in affinity (six-, seven- and 12-fold, respectively). The ratios of effects of these three mutations differed for compounds 227c89, 4030w92, and 619c89. The amino acid residues interacting with these pore-blocking drugs define a surface of IVS6 that is exposed to the pore and may rotate during gating.
AB - Voltage-gated sodium channels are blocked by local anesthetic and anticonvulsant drugs. A receptor site for local anesthetics has been defined in transmembrane segment S6 in domain IV (IVS6) of the α subunit, but the anticonvulsant lamotrigine and related compounds have more complex structures than local anesthetics and may interact with additional amino acid residues. Apparent KD values for inactivated-state block of rat brain type IIA sodium channels expressed in Xenopus oocytes were 31.9 μM, 17.3 μM, 3.7 μM and 10.3 μM for lamotrigine and compounds 227c89, 4030w92 and 619c89, respectively. Compound 619c89 was the strongest frequency-dependent blocker, which correlated with higher affinity and a five-fold slower recovery from drug block compared to lamotrigine. Examination of lamotrigine block of mutant sodium channel α subunits, in which alanine had been substituted for each individual amino acid in IVS6, identified mutations I1760A, F1764A and Y1771A as causing the largest reductions in affinity (six-, seven- and 12-fold, respectively). The ratios of effects of these three mutations differed for compounds 227c89, 4030w92, and 619c89. The amino acid residues interacting with these pore-blocking drugs define a surface of IVS6 that is exposed to the pore and may rotate during gating.
KW - Analgesic
KW - Anticonvulsant
KW - Brain
KW - Ion channel blocker
KW - Sodium channels
UR - http://www.scopus.com/inward/record.url?scp=0037373028&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037373028&partnerID=8YFLogxK
U2 - 10.1016/S0028-3908(02)00400-8
DO - 10.1016/S0028-3908(02)00400-8
M3 - Article
VL - 44
SP - 413
EP - 422
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
IS - 3
ER -