CGRP-II: nerve signaling peptide in the calcitonin family (β-CGRP)
A natural peptide made in nerves and the thyroid, part of the calcitonin family; used only as a lab research tool to study how the calcitonin receptor works.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Calcitonin gene-related peptide II (CGRP-II, also called β-CGRP) is a 37-amino acid signalling peptide belonging to the calcitonin/CGRP family — a group that includes calcitonin, α-CGRP (CGRP-I), amylin, and adrenomedullin, all of which act through class B G protein-coupled receptors (Hay and colleagues, British Journal of Pharmacology, 2018). CGRP-II is encoded by a separate gene from CGRP-I and differs from it by a small number of residues; both forms are expressed in neural tissue and the thyroid. The stored 37-residue sequence represents the backbone of equine CGRP-II, as cloned and characterized by Toribio and colleagues (Molecular and Cellular Endocrinology, 2003). Like all CGRP-family peptides, the active form carries a disulfide bond between the cysteine residues at positions 1 and 7, forming a ring at the N-terminus, and a C-terminal amide — neither modification is represented in the raw sequence shown here.
History
The existence of a second CGRP peptide, CGRP-II, was established when investigators found that the calcitonin/CGRP gene family was larger than the single CALC-I locus encoding calcitonin and α-CGRP: a separate gene (CALCB in humans) encodes β-CGRP. Comparative genomic work extended this characterization to non-human species; Toribio and colleagues reported the molecular cloning and tissue expression of equine calcitonin, CGRP-I, and CGRP-II in 2003, establishing that all three peptides are expressed in equine thyroid tissue with distinct patterns (Toribio and colleagues, Molecular and Cellular Endocrinology, 2003). The receptor pharmacology of the broader calcitonin/CGRP family was systematically reviewed and updated in the IUPHAR Review 25 by Hay and colleagues (British Journal of Pharmacology, 2018), which codified the nomenclature for CTR- and CLR-based receptor complexes that mediate the signalling of all family members.
What it does
CGRP-II acts through the same class B GPCR receptor systems as CGRP-I and calcitonin: the calcitonin receptor (CTR) and the calcitonin receptor-like receptor (CLR), whose pharmacological profiles are reshaped by heterodimerization with receptor activity-modifying proteins (RAMP1, RAMP2, or RAMP3). CTR paired with RAMP1, RAMP2, or RAMP3 generates the AMY1, AMY2, and AMY3 amylin receptor subtypes, respectively, and CLR paired with RAMP1 constitutes the canonical CGRP receptor (Hay and colleagues, 2018; Barwell and colleagues, British Journal of Pharmacology, 2012). Because CGRP-II's receptor selectivity profile closely parallels that of CGRP-I, it engages this same combinatorial receptor landscape. The calcitonin/CGRP receptor family has documented therapeutic relevance across a range of conditions including osteoporosis, migraine, cardiovascular disease, obesity, and diabetes (Barwell and colleagues, 2012). As a research tool, CGRP-II is used to probe receptor binding and compare activity against other calcitonin-family ligands including amylin; Lee and colleagues examined these cross-ligand interaction mechanisms at the calcitonin and amylin receptor systems at the molecular level (Journal of Biological Chemistry, 2016).
Evidence
- Human: No clinical trials of exogenous CGRP-II administration have been identified in the dossier. The broader CGRP receptor system — primarily via CGRP-I and its therapeutic blockers — has been extensively studied in human migraine and cardiovascular contexts.
- Animal: Equine CGRP-II was cloned from thyroid tissue and its expression pattern relative to CGRP-I and calcitonin was characterized in equine tissue (Toribio and colleagues, 2003). The calcitonin receptor (CTR) and related receptor complexes have been extensively studied in rodent models, including during osteoclast differentiation where RANKL-driven upregulation of CTR was documented in mouse bone marrow macrophages (Granholm and colleagues, Journal of Cellular Biochemistry, 2008).
- In vitro: Peptide interaction mechanisms at the calcitonin receptor and amylin receptor complexes, relevant to the CGRP-II binding context, have been characterized at the molecular level (Lee and colleagues, Journal of Biological Chemistry, 2016). CTR signalling downstream of calcitonin-family ligand binding — including cAMP and calcium pathway activation — has been described in cell-based systems (Pondel, International Journal of Experimental Pathology, 2000).
Known effects
- CTR and CLR receptor binding — Mechanistic; CGRP-II engages the same class B GPCR family members as other calcitonin-family peptides (Hay and colleagues, 2018; Barwell and colleagues, 2012)
- Cross-ligand pharmacology with amylin — Characterized at the receptor level for calcitonin/amylin receptor complexes (Lee and colleagues, 2016)
- Expression in thyroid and neural tissue — Demonstrated for equine CGRP-II by molecular cloning and tissue expression analysis (Toribio and colleagues, 2003)
Mechanism
CGRP-II signals through class B (secretin-family) GPCRs, sharing its receptor architecture with the rest of the calcitonin/CGRP family. The key feature of this family is that receptor pharmacology is determined not by the GPCR alone but by which RAMP it is co-expressed with: CTR/RAMP1, CTR/RAMP2, and CTR/RAMP3 give rise to the AMY1, AMY2, and AMY3 amylin receptor subtypes with different ligand selectivities, while CLR/RAMP1 constitutes the canonical CGRP receptor (Hay and colleagues, 2018). RAMP1 is upregulated during osteoclast differentiation alongside CTR; CLR and RAMP2/3 are expressed in M-CSF-stimulated macrophage precursors, with RANKL modifying the expression balance (Granholm and colleagues, 2008). CTR activation by calcitonin-family ligands stimulates cAMP and calcium signalling in osteoclasts, contributing to the regulation of bone resorption; this pathway was reviewed by Pondel (2000) in the context of calcitonin receptor biology. The molecular interactions between CGRP peptides, calcitonin, and amylin at shared receptor complexes — including the structural basis for cross-reactivity — were examined by Lee and colleagues (2016). Calcitonin-family receptor pharmacology more broadly — including the roles of CTR and CLR in osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine, and cardiovascular disease — was reviewed comprehensively by Barwell and colleagues (2012).
Related peptides
- α-CGRP (CGRP-I) — The closely related paralog encoded by CALC-I; primary endogenous agonist at the CLR/RAMP1 CGRP receptor; central pharmacological target in migraine biology.
- Beta-CGRP (rat) — The rat β-CGRP isoform; shares receptor targets with the equine CGRP-II sequence on this card; differs by one residue from rat α-CGRP.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Could equine beta-CGRP be used as the reference molecule to develop CGRP-blocking treatments tailored for horses?
If true, horses with painful vascular conditions like laminitis could eventually be treated with CGRP-targeting drugs designed for their own biology, rather than repurposed human medicines of uncertain efficacy.
Does the single Asp substitution at position 30 in equine beta-CGRP make it weaker at activating its receptor than human or rat CGRP?
If confirmed, this would explain why equine CGRP behaves differently from its human counterpart and could guide design of stronger CGRP-based drugs by showing exactly which position to optimise.
Do the two unique amino acids in equine beta-CGRP make it selectively active at CGRP receptors but weak at amylin receptors?
Understanding this selectivity could help design drugs that target pain and blood-vessel widening without the metabolic side effects linked to amylin receptor cross-activation, benefiting patients on CGRP therapies.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.5716715455055237 | openfold3-mlx |
| ranking score | 0.7234965562820435 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 1.038 | global PDE — lower = better |
| disorder | 0.272 | fraction disordered |
| chain pair ipTM (A, B) | 0.572 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | aedd8f3eb814e392… |
| hardware | apple_m4_base_16gb |
| mlx version | 0.31.1 |
| python | 3.14.3 |
| random seed | 42 |
| msa strategy | colabfold |
| diffusion samples | 1 |
| runtime | 463s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
python3 openfold3/run_openfold.py predict --query_json {query.json} --runner_yaml examples/example_runner_yamls/mlx_runner.yml --output_dir {output_dir} --num_diffusion_samples 1 ▸citationbibtex
@peptide{pep10646,
sequence = {SCNTATCVTHRLAGLLSRSGGVVKSNFVPTDVGSEAF},
target = {calcr},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}