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Vol. 53, Issue 2, 202-212, February 1998
Lehrstuhl für Zellphysiologie, Ruhr-Universität Bochum,
D-44780 Bochum, Germany (S.L., N.L., C.H.R.W., G.G., H.H.), and
Max-Planck-Institut für Psychatrie, Klinisches Institut, D-80804
München, Germany (R.R.)
Polymerase chain reaction and rapid amplification of cDNA ends were
used to isolate cDNAs encoding a 5-hydroxytryptamine3 (5-HT3) receptor subunit and its splice variants from
guinea pig intestine. The amino acid sequence predicted from this cDNA
is 81% homologous to the murine 5-HT3 receptor subunits
cloned from NCB20 and N1E-115 cells. The splice variants code for two
proteins differing by a deletion of six amino acids located in the
large intracellular loop between transmembrane domains M3 and M4. For characterization, the cloned 5-HT3 cDNA was expressed in
HEK 293 cells, and the electrophysiological and pharmacological
properties of the recombinant ion/channel/receptor complex were
investigated by patch clamping. Our data reveal that the cloned cDNAs
code for guinea pig 5-HT3 receptors, which functionally
assemble as homo-oligomers. The kinetic behavior of the ion channel and
its sensitivity to several agonists and antagonists were markedly different from those of the cloned 5-HT3 receptors from
mouse and human under similar experimental conditions. The agonists used were 5-hydroxytryptamine, 2-methyl-5-hydroxytryptamine,
1-phenylbiguanide (PBG), m-chlorophenylbiguanide, and
the antagonists tropisetron and metoclopramide. In addition, 5-HT, PBG,
and tropisetron were investigated through radioligand binding to
isolated membranes. Compared with the human and murine
5-HT3 receptors, the guinea pig receptor showed prolonged
desensitization kinetics. In addition, the guinea pig 5-HT3
receptor did not respond to the selective 5-HT3 receptor
agonist PBG. Construction of chimeric receptors between guinea pig and
human 5-HT3 receptor sequences localized the differences in
desensitization kinetics to the carboxyl-terminal domain and the ligand
binding site to the amino-terminal domain of the receptor protein.
Molecular determinants of the PBG binding site of the human
5-HT3 receptor were localized to a 28-amino-acid spanning
region adjacent to the M1 region.
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