Distinct Patterns of Internalization of Different Calcitonin Gene-Related Peptide Receptors.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is involved in the transmission of pain. Drugs targeting CGRP or a CGRP receptor are efficacious in the treatment of migraine. The canonical CGRP receptor is a complex of a G protein-coupled receptor, the calcitonin-like receptor (CLR), with an accessory protein, receptor activity-modifying protein 1 (RAMP1).

Molecular Mechanisms of Class B GPCR Activation: Insights from Adrenomedullin Receptors.

Adrenomedullin (AM) is a 52 amino acid peptide that plays a regulatory role in the vasculature. Receptors for AM comprise the class B G protein-coupled receptor, the calcitonin-like receptor (CLR), in complex with one of three receptor activity-modifying proteins (RAMPs). The C-terminus of AM is involved in binding to the extracellular domain of the receptor, while the N-terminus is proposed to interact with the juxtamembranous portion of the receptor to activate signaling.

New Insights into the Regulation of CGRP-Family Receptors.

The calcitonin gene-related peptide (CGRP) receptor system has emerged as an important drug target for migraine. This is highlighted by the recent regulatory approval of the first drug targeting the CGRP signalling pathway, the CGRP receptor antibody erenumab. The cellular compartments in which receptors are found affects drug access and whether they can exert their effects.

Photoaffinity Cross-Linking and Unnatural Amino Acid Mutagenesis Reveal Insights into Calcitonin Gene-Related Peptide Binding to the Calcitonin Receptor-like Receptor/Receptor Activity-Modifying Protein 1 (CLR/RAMP1) Complex.

Calcitonin gene-related peptide (CGRP) binds to the complex of the calcitonin receptor-like receptor (CLR) with receptor activity-modifying protein 1 (RAMP1). How CGRP interacts with the transmembrane domain (including the extracellular loops) of this family B receptor remains unclear. In this study, a photoaffinity cross-linker, p-azido l-phenylalanine (azF), was incorporated into CLR, chiefly in the second extracellular loop (ECL2) using genetic code expansion and unnatural amino acid mutagenesis.

Receptor Activity Modifying Proteins Have Limited Effects on the Class B G Protein-Coupled Receptor Calcitonin Receptor-Like Receptor Stalk.

The calcitonin receptor-like receptor (CLR) is a class B G protein-coupled receptor (GPCR) that forms the basis of three pharmacologically distinct receptors, the calcitonin gene-related peptide (CGRP) receptor, and two adrenomedullin (AM) receptors. These three receptors are created by CLR interacting with three receptor activity-modifying proteins (RAMPs). Class B GPCRs have an N-terminal extracellular domain (ECD) and transmembrane bundle that are both important for binding endogenous ligands.

N-Glycosylation of Asparagine 130 in the Extracellular Domain of the Human Calcitonin Receptor Significantly Increases Peptide Hormone Affinity.

The calcitonin receptor (CTR) is a class B G protein-coupled receptor that is activated by the peptide hormones calcitonin and amylin. Calcitonin regulates bone remodeling through CTR, whereas amylin regulates blood glucose and food intake by activating CTR in complex with receptor activity-modifying proteins (RAMPs). These receptors are targeted clinically for the treatment of osteoporosis and diabetes.

Erratum: An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology.

[This corrects the article DOI: 10.1038/celldisc.2016.

An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology.

G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor activity-modifying proteins (RAMPs).

Receptor activity-modifying proteins; multifunctional G protein-coupled receptor accessory proteins.

Receptor activity-modifying proteins (RAMPs) are single pass membrane proteins initially identified by their ability to determine the pharmacology of the calcitonin receptor-like receptor (CLR), a family B G protein-coupled receptor (GPCR). It is now known that RAMPs can interact with a much wider range of GPCRs. This review considers recent developments on the structure of the complexes formed between the extracellular domains (ECDs) of CLR and RAMP1 or RAMP2 as these provide insights as to how the RAMPs direct ligand binding.

Receptor Activity-modifying Proteins 2 and 3 Generate Adrenomedullin Receptor Subtypes with Distinct Molecular Properties.

Adrenomedullin (AM) is a peptide hormone with numerous effects in the vascular systems. AM signals through the AM1 and AM2 receptors formed by the obligate heterodimerization of a G protein-coupled receptor, the calcitonin receptor-like receptor (CLR), and receptor activity-modifying proteins 2 and 3 (RAMP2 and RAMP3), respectively. These different CLR-RAMP interactions yield discrete receptor pharmacology and physiological effects.

Activity of pramlintide, rat and human amylin but not Aβ1-42 at human amylin receptors.

Amylin is a neuroendocrine hormone involved in glucose regulation. An amylin analog, pramlintide, is used to treat insulin-requiring diabetes. Its anorexigenic actions give it potential as an obesity treatment.

Structural insights into RAMP modification of secretin family G protein-coupled receptors: implications for drug development.

Secretin family G protein-coupled receptors (GPCRs) are important therapeutic targets for migraine, diabetes, bone disorders, inflammatory disorders and cardiovascular disease. They possess a large N-terminal extracellular domain (ECD) known to be the primary ligand-binding determinant. Structural determination of several secretin family GPCR ECDs in complex with peptide ligands has been achieved recently, providing insight into the molecular determinants of hormone binding.

Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs?

The calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR) are two of the 15 human family B (or Secretin-like) GPCRs. CTR and CLR are of considerable biological interest as their pharmacology is moulded by interactions with receptor activity-modifying proteins. They also have therapeutic relevance for many conditions, such as osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine and cardiovascular disease.

A key role for tryptophan 84 in receptor activity-modifying protein 1 in the amylin 1 receptor.

Amylin (Amy) receptors are complexes of the calcitonin receptor with receptor activity-modifying proteins. RAMP1 with the calcitonin receptor forms the AMY(1) receptor; the insert negative isoform of the calcitonin receptor in this complex makes the AMY(1(a)) receptor. This receptor has high affinity for Amy and the related peptide calcitonin gene-related peptide (CGRP).