期刊
BIOPHYSICAL JOURNAL
卷 79, 期 3, 页码 1379-1387出版社
BIOPHYSICAL SOCIETY
DOI: 10.1016/S0006-3495(00)76390-9
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- NIGMS NIH HHS [GM48090, GM35401] Funding Source: Medline
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM048090, R01GM035401] Funding Source: NIH RePORTER
Batrachotoxin (BTX) alters the gating of voltage-gated Na+ channels and causes these channels to open persistently, whereas local anesthetics (LAs) block Na+ conductance. The BTX and LA receptors have been mapped to several common residues in D1-S6 and D4-S6 segments of the Na+ channel alpha-subunit. We substituted individual residues with lysine in homologous segment D3-S6 of the rat muscle mu 1 Na+ channel from F1274 to N1281 to determine whether additional residues are involved in BTX and LA binding. Two mutant channels, mu 1-S1276K and mu 1-L1280K, when expressed in mammalian cells, become completely resistant to 5 mu M BTX during repetitive pulses. The activation and/or fast inactivation gating of these mutants is substantially different from that of wild type. These mutants also display similar to 10-20-fold reduction in bupivacaine affinity toward their inactivated state but show only approximately twofold affinity changes toward their resting state. These results demonstrate that residues mu 1-S1276 and mu 1-L1280 in D3-S6 are critical for both BTX and LA binding interactions. We propose that LAs interact readily with these residues from D3-S6 along with those from D1-S6 and D4-S6 in close proximity when the Na+ channel is in its inactivated state. Implications of this state-dependent binding model for the S6 alignment are discussed.
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