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Research ArticleArticle

Identification of Conserved Aromatic Residues Essential for Agonist Binding and Second Messenger Production at 5-Hydroxytryptamine2A Receptors

B. L. Roth, M. Shoham, M. S. Choudhary and N. Khan
Molecular Pharmacology August 1997, 52 (2) 259-266; DOI: https://doi.org/10.1124/mol.52.2.259
B. L. Roth
Departments of Psychiatry and Biochemistry, Case Western Reserve University Medical School, Cleveland, Ohio 44106-4935
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M. Shoham
Departments of Psychiatry and Biochemistry, Case Western Reserve University Medical School, Cleveland, Ohio 44106-4935
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M. S. Choudhary
Departments of Psychiatry and Biochemistry, Case Western Reserve University Medical School, Cleveland, Ohio 44106-4935
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N. Khan
Departments of Psychiatry and Biochemistry, Case Western Reserve University Medical School, Cleveland, Ohio 44106-4935
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Abstract

Several models of agonist binding to G protein-coupled 5-hydroxytryptamine [5-HT] (serotonin) receptors have highlighted the potential importance of highly conserved aromatic residues for ligand binding and agonist efficacy. In this study, we tested these models by constructing and characterizing a number of point mutations of conserved and nonconserved aromatic residues using the 5-HT2A receptor as a model system. Mutations of three highly conserved tryptophans (W200A, W336A, and W367A) proposed to reside near the binding pocket markedly reduced agonist affinity and efficacy at 5-HT2A receptors. Mutations of two other highly conserved aromatic residues postulated to be near the agonist binding site (F340L and Y370A) also had dramatic effects on agonist binding and efficacy. Point mutations of neighboring conserved phenylalanines (F339L and F365L) had minimal effects on agonist binding, although the F365L mutation diminished agonist efficacy. Finally, mutations of two nonconserved aromatic residues (F125L and F383A) not predicted to be near the binding pocket had no effects on agonist binding, potency, or efficacy. Our results are best explained by models that suggest that helices III, V, VI, and VII can form a unit of interacting helices in which highly conserved aromatic residues are oriented toward the center of the helical aggregate to form an aromatic pocket. In addition, our novel results identify a series of aromatic residues essential for agonist-induced second messenger production. These results demonstrate that highly conserved aromatic residues residing in neighboring helices provide the optimum environment for both agonist binding and activation of 5-HT2A receptors.

Footnotes

    • Received January 10, 1997.
    • Accepted May 7, 1997.
  • Send reprint requests to: Dr. Bryan L. Roth, Dept. of Biochemistry, Room W438, 10900 Euclid Avenue, Cleveland, OH 44106-4935. E-mail: roth{at}biocserver.cwru.edu

  • This work was supported in part by National Institutes of Health Grants GM52213 (M.H.) and MH01366 and a grant from the Scottish Rite Schizophrenia Research Foundation (B.L.R.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 52 (2)
Molecular Pharmacology
Vol. 52, Issue 2
1 Aug 1997
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Research ArticleArticle

Identification of Conserved Aromatic Residues Essential for Agonist Binding and Second Messenger Production at 5-Hydroxytryptamine2A Receptors

B. L. Roth, M. Shoham, M. S. Choudhary and N. Khan
Molecular Pharmacology August 1, 1997, 52 (2) 259-266; DOI: https://doi.org/10.1124/mol.52.2.259

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Research ArticleArticle

Identification of Conserved Aromatic Residues Essential for Agonist Binding and Second Messenger Production at 5-Hydroxytryptamine2A Receptors

B. L. Roth, M. Shoham, M. S. Choudhary and N. Khan
Molecular Pharmacology August 1, 1997, 52 (2) 259-266; DOI: https://doi.org/10.1124/mol.52.2.259
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