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Research ArticleArticle

Molecular Cloning, Functional Expression, and Pharmacological Characterization of 5-Hydroxytryptamine3 Receptor cDNA and Its Splice Variants from Guinea Pig

Silke Lankiewicz, Nicole Lobitz, Christian H. R. Wetzel, Rainer Rupprecht, Günter Gisselmann and Hanns Hatt
Molecular Pharmacology February 1998, 53 (2) 202-212; DOI: https://doi.org/10.1124/mol.53.2.202
Silke Lankiewicz
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Nicole Lobitz
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Christian H. R. Wetzel
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Rainer Rupprecht
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Günter Gisselmann
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Hanns Hatt
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Abstract

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-HT3receptor 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.

Footnotes

    • Received June 20, 1997.
    • Accepted October 9, 1997.
  • Send reprint requests to: Dr. Hanns Hatt, Fakultät für Biologie, Lehrstuhl für Zellphysiologie, Ruhr-Universitätsstr. 150, D-44780 Bochum, Germany. E-mail:hatt{at}cphys.ruhr-uni-bochum.de

  • This work was supported in part by the Gerhard-Heß-Programm of the Deutsche Forschungsgemeinschaft (R.R.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (2)
Molecular Pharmacology
Vol. 53, Issue 2
1 Feb 1998
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Research ArticleArticle

Molecular Cloning, Functional Expression, and Pharmacological Characterization of 5-Hydroxytryptamine3 Receptor cDNA and Its Splice Variants from Guinea Pig

Silke Lankiewicz, Nicole Lobitz, Christian H. R. Wetzel, Rainer Rupprecht, Günter Gisselmann and Hanns Hatt
Molecular Pharmacology February 1, 1998, 53 (2) 202-212; DOI: https://doi.org/10.1124/mol.53.2.202

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Research ArticleArticle

Molecular Cloning, Functional Expression, and Pharmacological Characterization of 5-Hydroxytryptamine3 Receptor cDNA and Its Splice Variants from Guinea Pig

Silke Lankiewicz, Nicole Lobitz, Christian H. R. Wetzel, Rainer Rupprecht, Günter Gisselmann and Hanns Hatt
Molecular Pharmacology February 1, 1998, 53 (2) 202-212; DOI: https://doi.org/10.1124/mol.53.2.202
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