ArticleMolecular pharmacology2009
Functional importance of a structurally distinct homodimeric complex of the family B G protein-coupled secretin receptor.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 52 citations in OpenAlex.
- Mechanistic insights from the atomic-level quaternary structure of short-lived GPCR oligomers of the human secretin receptor in live cells.Communications biology · 2025Article
- Mechanistic insights from the atomic-level quaternary structure of short-lived GPCR oligomers in live cells.Research square · 2024Article
- Impact of secretin receptor homo-dimerization on natural ligand binding.Nature communications · 2024Article
- New Insights into the Structure and Function of Class B1 GPCRs.Endocrine reviews · 2023Article
- Structural Basis for Allosteric Modulation of Class B G Protein-Coupled Receptors.Annual review of pharmacology and toxicology · 2020Review
- Actin cytoskeleton-dependent regulation of corticotropin-releasing factor receptor heteromers.Molecular biology of the cell · 2017Article
- Spatial intensity distribution analysis quantifies the extent and regulation of homodimerization of the secretin receptor.The Biochemical journal · 2017Article
- Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes.Pharmacological reviews · 2016Review
- Structure and Function of Cross-class Complexes of G Protein-coupled Secretin and Angiotensin 1a Receptors.The Journal of biological chemistry · 2016Article
- Transmembrane signal transduction by peptide hormones via family B G protein-coupled receptors.Frontiers in pharmacology · 2015Review
- The class B G-protein-coupled GLP-1 receptor: an important target for the treatment of type-2 diabetes mellitus.International journal of obesity supplements · 2014Review
- Transmembrane peptides as unique tools to demonstrate the in vivo action of a cross-class GPCR heterocomplex.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2014Article
- Role of CGRP-receptor component protein (RCP) in CLR/RAMP function.Current protein & peptide science · 2013Review
- Emerging paradigms in GPCR allostery: implications for drug discovery.Nature reviews. Drug discovery · 2013Review
- A novel approach to quantify G-protein-coupled receptor dimerization equilibrium using bioluminescence resonance energy transfer.Methods in molecular biology (Clifton, N.J.) · 2013Article
- Mapping spatial approximations between the amino terminus of secretin and each of the extracellular loops of its receptor using cysteine trapping.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2012Article
- Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs?British journal of pharmacology · 2012Review
- Consequences of splice variation on Secretin family G protein-coupled receptor function.British journal of pharmacology · 2012Review
- Ligand binding and activation of the secretin receptor, a prototypic family B G protein-coupled receptor.British journal of pharmacology · 2012Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Oligomerization of G protein-coupled receptors has been described, but its structural basis and functional importance have been inconsistent. Here, we demonstrate that the agonist occupied wild-type secretin receptor is predominantly in a guanine nucleotide-sensitive high-affinity state and exhibits negative cooperativity, whereas the monomeric receptor is primarily in a guanine nucleotide-insensitive lower affinity state. We previously demonstrated constitutive homodimerization of this receptor through the lipid-exposed face of transmembrane (TM) IV. We now use cysteine-scanning mutagenesis of 14 TM IV residues, bioluminescence resonance energy transfer (BRET), and functional analysis to map spatial approximations and functional importance of specific residues in this complex. All, except for three helix-facing mutants, trafficked to the cell surface, where secretin was shown to bind and elicit cAMP production. Cells expressing complementary-tagged receptors were treated with cuprous phenanthroline to establish disulfide bonds between spatially approximated cysteines. BRET was measured as an indication of receptor oligomerization and was repeated after competitive disruption of oligomers with TM IV peptide to distinguish covalent from noncovalent associations. Although all constructs generated a significant BRET signal, this was disrupted by peptide in all except for single-site mutants replacing five residues with cysteine. Of these, covalent stabilization of receptor homodimers through positions of Gly(243), Ile(247), and Ala(250) resulted in a GTP-sensitive high-affinity state of the receptor, whereas the same procedure with Ala(246) and Phe(240) mutants resulted in a GTP-insensitive lower affinity state. We propose the existence of a functionally important, structurally specific high-affinity dimeric state of the secretin receptor, which may be typical of family B G protein-coupled receptors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.