ArticleBritish journal of pharmacology2014
Structure-activity relationships of the N-terminus of calcitonin gene-related peptide: key roles of alanine-5 and threonine-6 in receptor activation.
Article in British journal of pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 33 citations in OpenAlex.
- Calcitonin Gene-Related Peptide (CGRP): Biology, Signaling, Pathophysiological Roles, and Therapeutic Applications.International journal of molecular sciences · 2026Review
- Extracellular bimolecular fluorescence complementation for investigating membrane protein dimerization: a proof of concept using class B GPCRs.Bioscience reports · 2024Article
- Cryo-EM Structure of the Human Amylin 1 Receptor in Complex with CGRP and Gs Protein.Biochemistry · 2024Article
- Benzenesulfonamide Analogs: Synthesis, Anti-GBM Activity and Pharmacoprofiling.International journal of molecular sciences · 2023Article
- CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond.Physiological reviews · 2023Review
- Expression of the CGRP Family of Neuropeptides and their Receptors in the Trigeminal Ganglion.Journal of molecular neuroscience : MN · 2020Article
- Molecular Mechanisms of Class B GPCR Activation: Insights from Adrenomedullin Receptors.ACS pharmacology & translational science · 2020Article
- Distinct Patterns of Internalization of Different Calcitonin Gene-Related Peptide Receptors.ACS pharmacology & translational science · 2020Article
- Molecular Signature for Receptor Engagement in the Metabolic Peptide Hormone Amylin.ACS pharmacology & translational science · 2018Article
- Cryo-EM structure of the active, GNature · 2018Article
- CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured.Cephalalgia : an international journal of headache · 2018Article
- Amylin structure-function relationships and receptor pharmacology: implications for amylin mimetic drug development.British journal of pharmacology · 2016Review
- An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology.Cell discovery · 2016Article
- Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles.Annual review of pharmacology and toxicology · 2016Review
- Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
background and purposeThe N-terminus of calcitonin gene-related peptide (CGRP) is important for receptor activation, especially the disulphide-bonded ring (residues 1-7). However, the roles of individual amino acids within this region have not been examined and so the molecular determinants of agonism are unknown. This study has examined the role of residues 1, 3-6 and 8-9, excluding Cys-2 and Cys-7. EXPERIMENTAL APPROACH: CGRP derivatives were substituted with either cysteine or alanine; further residues were introduced at position 6. Their affinity was measured by radioligand binding and their efficacy by measuring cAMP production in SK-N-MC cells and β-arrestin 2 translocation in CHO-K1 cells at the CGRP receptor. KEY
resultsSubstitution of Ala-5 by cysteine reduced affinity 270-fold and reduced efficacy for production of cAMP in SK-N-MCs. Potency at β-arrestin translocation was reduced by ninefold. Substitution of Thr-6 by cysteine destroyed all measurable efficacy of both cAMP and β-arrestin responses; substitution with either alanine or serine impaired potency. Substitutions at positions 1, 4, 8 and 9 resulted in approximately 10-fold reductions in potency at both responses. Similar observations were made at a second CGRP-activated receptor, the AMY(1(a)) receptor. CONCLUSIONS AND IMPLICATIONS: Ala-5 and Thr-6 are key determinants of agonist activity for CGRP. Ala-5 is also very important for receptor binding. Residues outside of the 1-7 ring also contribute to agonist activity.
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