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  Identification of Neurohypophysial Hormone Receptor Domains Involved in Ligand Binding and G Protein Coupling

Postina, R., Kojro, E., & Fahrenholz, F. (1998). Identification of Neurohypophysial Hormone Receptor Domains Involved in Ligand Binding and G Protein Coupling. In H. Zingg, C. Bourque, & D. Bichet (Eds.), Advances in Experimental Medicine and Biology (pp. 371-385 ). Boston, MA, USA: Springer.

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Item Permalink: https://hdl.handle.net/21.11116/0000-0007-A7B8-D Version Permalink: https://hdl.handle.net/21.11116/0000-0007-A7B9-C
Genre: Book Chapter

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 Creators:
Postina, Rolf1, Author           
Kojro, Elzbieta2, Author           
Fahrenholz, Falk2, Author           
Affiliations:
1Department of Biophysical Chemistry, Max Planck Institute of Biophysics, Max Planck Society, ou_2068289              
2Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society, ou_2068290              

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 Abstract: Chimeric vasopressin V2/OT receptors were constructed and investigated to identify receptor regions involved in ligand binding or G protein coupling. The fusion sites for one series of hybrid receptors were either located at the C-terminal end of the third extracellular domain or in the centre of the third transmembrane helix, respectively. In each pair of the resulting symmetrical hybrids only one receptor was able to bind arginine vasopressin (AVP) and/or oxytocin (OT). In both cases a major part of the vasopressin V2, receptor (V2R) was needed for ligand binding. A chimeric OT/V2 receptor including Of receptor (OTR) sequences from its N-terminus to the middle of transmembrane region three showed both high-affinity OT binding (Ki = 3 nM) and activation of the adenylyl cyclase. In contrast, a hybrid containing OTR sequences reaching from transmembrane helix five to its C-terminus showed the V2 receptors ligand binding profile and was unable to couple to Gαs. These results indicate (i) that the third and/or the fourth intracellular domain of the V2R are involved in G protein coupling and (ii) for high-affinity OT binding the N-terminal third of the OTR plays an important role.

By detailed binding studies on a second series of chimeric V2/OT receptors with AVP, OT and the two hybrid hormone derivatives arginine vasotocin and oxypressin it was further demonstrated that the first two extracellular domains of the OTR are involved in binding to the C-terminal tripeptide of OT. Moreover, the third extracellular domain of the OTR is able to contact the cyclic part of OT and the fourth outer domain does not interact with the two variable amino acid residues of AVP and OT. Thus, the first three extracellu­lar domains of the OTR provide an essential part of the OT binding site. The other part is most probably contributed by the OTRs transmembrane helices 3 and 4.

Photoaffinity labeling and ligand binding studies demonstrated that the binding site for the OT antagonist d(CH2)5[Tyr(Me)2, Thr4, Orn8, Tyr9]vasotocin is located in the heli­ces 1, 2 and 7. Our results provide evidence for the existence of separate domains of a peptide hormone receptor involved in binding and selectivity for agonists and peptide an­tagonists.

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Language(s): eng - English
 Dates: 1998
 Publication Status: Issued
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1007/978-1-4615-4871-3_48
 Degree: -

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Title: Advances in Experimental Medicine and Biology
  Subtitle : Vasopressin and Oxytocin
  Subtitle : Molecular, Cellular, and Clinical Advances
Source Genre: Series
 Creator(s):
Zingg, H.H.1, Editor
Bourque, C.W.1, Editor
Bichet, D.G.2, Editor
Affiliations:
1 McGill University, Montreal, Quebec, Canada, ou_persistent22            
2 University of Montreal, Montreal, Quebec, Canada, ou_persistent22            
Publ. Info: Boston, MA, USA : Springer
Pages: 483 Volume / Issue: 449 Sequence Number: - Start / End Page: 371 - 385 Identifier: ISBN: 978-1-4613-7210-3
DOI: 10.1007/978-1-4615-4871-3