A role for the Val291 residue within the transmembrane domain 2 in diltiazem- and TMB-8 [3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester]-mediated 5-hydroxytryptamine type 3A receptor regulations

Title
A role for the Val291 residue within the transmembrane domain 2 in diltiazem- and TMB-8 [3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester]-mediated 5-hydroxytryptamine type 3A receptor regulations
Authors
이병환최선혜표미경신태준황성희김보라이준호임혜원김형춘나승열
Keywords
diltiazem; 5-hydroxytryptamine type 3A receptor; common interaction site; 3,4,5-trimethoxybenzoic acid
Issue Date
2009-05
Publisher
Biological & pharmaceutical bulletin
Citation
VOL 32, NO 5, 861-867
Abstract
Previous reports have shown that diltiazem and TMB, calcium channel antagonists, inhibit 5-hydroxytryptamine type 3A (5-HT3A) receptor-mediated currents (I5-HT) in cell lines and in heterologously expressed Xenopus oocytes. In the present study, we sought to elucidate the molecular mechanisms underlying diltiazem- and TMBinduced 5-HT3A receptor regulations. We used the two-microelectrode voltage clamp technique to investigate the effect of diltiazem and TMB on 5-HT-mediated ion currents in Xenopus oocytes expressing wild-type or 5-HT3A receptors harboring mutations in the gating pore region of transmembrane domain 2 (TM2). In oocytes expressing wild-type 5-HT3A receptors, diltiazem and TMB dose-dependently inhibited peak I5-HT with an IC50 of 71.4 4.9 and 4.5 0.3mM, respectively. Among various mutants of TM2, mutation V291A greatly attenuated and abolished the TMB- and diltiazem-induced inhibition of peak I5-HT, respectively. Mutation V291A also induced constitutively active ion currents in the absence of 5-HT. Diltiazem and TMB inhibited constitutively active ion currents in a dose-dependent manner. The IC50 values of constitutively active ion currents in V291A receptors were 165.3 11.1 and 6.6 0.5mM for diltiazem and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8), respectively. Results of site-directed mutagenesis experiments suggest that the Val291 residue could be a candidate for common interaction site for diltiazem- and TMB-8-mediated 5-HT3A receptor regulations.
URI
http://pubs.kist.re.kr/handle/201004/40938
ISSN
0918-6158
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