CaltechAUTHORS
  A Caltech Library Service

Probing the Role of a Conserved M1 Proline Residue in 5-Hydroxytryptamine₃ Receptor Gating

Dang, Hong and England, Pamela M. and Farivar, S. Sarah and Dougherty, Dennis A. and Lester, Henry A. (2000) Probing the Role of a Conserved M1 Proline Residue in 5-Hydroxytryptamine₃ Receptor Gating. Molecular Pharmacology, 57 (6). pp. 1114-1122. ISSN 0026-895X. https://resolver.caltech.edu/CaltechAUTHORS:20200513-070503095

Full text is not posted in this repository. Consult Related URLs below.

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20200513-070503095

Abstract

A conserved proline residue is found in the first transmembrane domain (M1) of every subunit in the ligand-gated ion channel superfamily. The position of this proline between the N-terminal extracellular agonist binding and the second transmembrane (M2) channel lining domains in the primary sequence suggests its possible involvement in the gating of the receptor. Replacing this proline with alanine, glycine, or leucine in the 5-hydroxytryptamine (5-HT)_(3A) homomeric receptors expressed in Xenopus laevis oocytes resulted in the absence of 5-HT-induced whole-cell currents, although there were normal levels of specific surface [³H]granisetron ([³H]BRL-43694) binding sites. To determine what properties of the conserved proline are critical for the function of the channel, two imino acids and an α-hydroxy acid were incorporated at the proline position using the nonsense suppression method.trans-3-Methyl-proline, pipecolic acid, and leucic acid were able to replace the conserved proline to produce active channels with EC₅₀ values similar to that for the wild-type receptor. These trends are preserved in the heteromeric receptors consisting of 5-HT_(3A) and 5-HT_(3B) subunits in oocytes. The prominent common feature among these residues and proline is the lack of hydrogen bond donor activity, potentially resulting in a flexible secondary structure in the M1 region. Thus, lack of hydrogen bond donor activity may be a key element in channel gating and may explain the high degree of conservation of this M1 proline.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://molpharm.aspetjournals.org/content/57/6/1114PublisherArticle
ORCID:
AuthorORCID
Dougherty, Dennis A.0000-0003-1464-2461
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2000 The American Society for Pharmacology and Experimental Therapeutics. Received December 9, 1999; accepted February 12, 2000. We thank Justin Gallivan, Scott Silverman, and Wenge Zhong for sharing synthetic dCA amino acid analogs and Hairong Li for preparingX. laevis oocytes used in our experiments. We also thank Drs. D. Julius (UCSF) and E. Kirkness (TIGR) for the 5-HT₃ cDNA clones and Dr. P. Schultz for P3m. This work was supported by National Institutes of Health Grants MH49176, NS34407, and NS10305.
Funders:
Funding AgencyGrant Number
NIHMH49176
NIHNS34407
NIHNS10305
Issue or Number:6
Record Number:CaltechAUTHORS:20200513-070503095
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200513-070503095
Official Citation:Probing the Role of a Conserved M1 Proline Residue in 5-Hydroxytryptamine3 Receptor Gating. Hong Dang, Pamela M. England, S. Sarah Farivar, Dennis A. Dougherty and Henry A. Lester. Molecular Pharmacology June 1, 2000, 57 (6) 1114-1122
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103161
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:13 May 2020 15:31
Last Modified:13 May 2020 15:31

Repository Staff Only: item control page