Calcitonin Receptor Protein

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Calcitonin Receptor Protein

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Calcitonin Receptor Protein

Overview

Calcitonin Receptor (CALCR) is a Class B (secretin) G protein-coupled receptor (GPCR) that binds calcitonin, calcitonin gene-related peptide (CGRP), amylin, and related peptides. While primarily studied in bone metabolism and migraine, CALCR is increasingly recognized for its roles in neuroprotection, pain modulation, and neuroinflammatory processes relevant to Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions [1](https://doi.org/10.1016/j.pneurobio.2019.04.004). The receptor is encoded by the [CALCR](/genes/calcr) gene and signals through multiple G protein pathways to regulate diverse physiological processes in the central and peripheral nervous systems.

Protein Infobox

<div class="infobox infobox-protein">
<table>
<tr><th>Protein Name</th><td>Calcitonin Receptor (CALCR)</td></tr>
<tr><th>Gene</th><td>[CALCR](/genes/calcr)</td></tr>
<tr><th>UniProt ID</th><td>[P30988](https://www.uniprot.org/uniprot/P30988)</td></tr>
<tr><th>PDB Structures</th><td>7XBW, 7XBY, 6X10</td></tr>
<tr><th>Molecular Weight</th><td>~64 kDa (n glycosylated)</td></tr>
<tr><th>Subcellular Localization</th><td>Plasma membrane</td></tr>
<tr><th>Protein Family</th><td>Class B GPCR (Secretin family)</td></tr>
<tr><th>Expression</th><td>Neurons, glia, pituitary, bone, kidney</td></tr>
</table>
</div>

Structural Features

Receptor Architecture

...

Calcitonin Receptor Protein

Overview

Calcitonin Receptor (CALCR) is a Class B (secretin) G protein-coupled receptor (GPCR) that binds calcitonin, calcitonin gene-related peptide (CGRP), amylin, and related peptides. While primarily studied in bone metabolism and migraine, CALCR is increasingly recognized for its roles in neuroprotection, pain modulation, and neuroinflammatory processes relevant to Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions [1](https://doi.org/10.1016/j.pneurobio.2019.04.004). The receptor is encoded by the [CALCR](/genes/calcr) gene and signals through multiple G protein pathways to regulate diverse physiological processes in the central and peripheral nervous systems.

Protein Infobox

<div class="infobox infobox-protein">
<table>
<tr><th>Protein Name</th><td>Calcitonin Receptor (CALCR)</td></tr>
<tr><th>Gene</th><td>[CALCR](/genes/calcr)</td></tr>
<tr><th>UniProt ID</th><td>[P30988](https://www.uniprot.org/uniprot/P30988)</td></tr>
<tr><th>PDB Structures</th><td>7XBW, 7XBY, 6X10</td></tr>
<tr><th>Molecular Weight</th><td>~64 kDa (n glycosylated)</td></tr>
<tr><th>Subcellular Localization</th><td>Plasma membrane</td></tr>
<tr><th>Protein Family</th><td>Class B GPCR (Secretin family)</td></tr>
<tr><th>Expression</th><td>Neurons, glia, pituitary, bone, kidney</td></tr>
</table>
</div>

Structural Features

Receptor Architecture

The CALCR protein possesses the characteristic architecture of Class B GPCRs, consisting of distinct domains optimized for peptide hormone binding and signal transduction [10](https://doi.org/10.1124/pr.119.018531).

N-terminal Extracellular Domain (ECD): The large ECD (approximately 150 amino acids) contains multiple disulfide bonds and a conserved fold that serves as the primary ligand-binding site. This domain recognizes the C-terminal region of peptide ligands including calcitonin, CGRP, and amylin. The ECD adopts a unique fold characterized by a short α-helix and a β-hairpin, creating a binding pocket that achieves high-affinity ligand recognition through a network of hydrogen bonds and hydrophobic interactions.
Seven Transmembrane Domain (TMD): Like other GPCRs, CALCR contains seven transmembrane helices (TM1-TM7) connected by three extracellular loops (ECL1-3) and three intracellular loops (ICL1-3). The transmembrane domain adopts the classic seven-helix bundle conformation that undergoes conformational changes upon ligand binding, enabling coupling to intracellular G proteins. The Class B signature includes a conserved proline in TM6 and specific residues in the DRY motif at the boundary of TM3 and ICL2.
C-terminal Intracellular Domain: The C-terminal tail (approximately 80 amino acids) contains serine/threonine residues that serve as phosphorylation sites for GPCR kinases (GRKs). This domain also contains motifs important for receptor internalization and desensitization through β-arrestin recruitment.

Ligand-Binding Pocket Architecture

The ligand-binding mechanism involves two distinct binding sites:

Primary Binding Site (ECD): The extracellular domain provides the primary high-affinity binding interface for peptide ligands. Structural studies have revealed that the C-terminal "message" region of CGRP engages the ECD, while the N-terminal region interacts with the transmembrane domain to trigger signal transduction.

Secondary Binding Site (TMD): The transmembrane domain contributes to ligand recognition, particularly for small molecule antagonists (gepants). The interface between the ECD and TMD creates a complex binding pocket that can be targeted by different drug classes.

Post-translational Modifications

CALCR undergoes several important post-translational modifications:

N-linked Glycosylation: The extracellular domain contains multiple N-glycosylation sites that affect receptor folding, trafficking, and ligand-binding affinity
Disulfide Bonds: Conserved disulfide bonds in the ECD maintain structural stability
Palmitoylation: C-terminal cysteine residues undergo S-acylation, anchoring the receptor in the plasma membrane

Normal Physiological Function

Signaling Pathways

CALCR activates multiple intracellular signaling cascades through coupling to different G protein subtypes [8](https://doi.org/10.1016/j.celrep.2022.110123):

Gs-coupled cAMP/PKA Pathway

Primary signaling pathway upon ligand binding
Activates adenylyl cyclase, increasing intracellular cAMP
Promotes PKA activation and downstream phosphorylation events
Mediates bone resorption inhibition (calcitonin) and neuromodulation (CGRP)

Gq/11-coupled PLC/IP3/DAG Pathway

Activates phospholipase C (PLC)
Generates inositol trisphosphate (IP3) and diacylglycerol (DAG)
Increases intracellular calcium release
Involved in pain signaling and vasodilation

Gβγ-mediated Pathways

Activates PI3K/Akt signaling
Modulates ion channel function
Contributes to neuroprotective effects

β-arrestin Signaling

Independent of G protein signaling
Mediates receptor internalization
Activates MAPK pathways (ERK1/2, p38)

Tissue Distribution and Function

Nervous System

In the central nervous system, CALCR (particularly as the CGRP receptor complex) is expressed in regions involved in pain processing, mood, and autonomic function:

Trigeminal Nucleus Caudalis: Primary site for processing craniofacial pain
Hypothalamus: Regulates stress responses and autonomic function
Locus Coeruleus: Modulates arousal and pain perception
Periaqueductal Gray: Involved in descending pain inhibition
Hippocampus: Expressed in CA1/CA3 regions, implicated in memory

Peripheral Nervous System

Dorsal Root Ganglion (DRG): Primary sensory neurons expressing CALCR
CGRP-positive afferents: Involved in neurogenic inflammation
Enteric nervous system: Modulates gastrointestinal function

Bone and Mineral Metabolism

Osteoclasts: Calcitonin binding inhibits bone resorption
Kidney: Regulates calcium reabsorption
Parathyroid: Feedback regulation of calcitonin secretion

Role in Neurodegenerative Diseases

Migraine

The CGRP receptor (CALCR + RAMP1) is central to migraine pathophysiology [2](https://doi.org/10.1038/s41582-023-00765-7):

Pathophysiology

CGRP is released during migraine attacks from trigeminal afferents
CGRP causes meningeal vasodilation and neurogenic inflammation
Receptor activation on trigeminal nociceptors propagates pain signals
Temporal correlation between CGRP levels and migraine attacks

Therapeutic Targeting [5](https://doi.org/10.1016/S1474-4422(24)00120-5)

CGRP Monoclonal Antibodies (Preventive therapy):

Erenumab: Anti-CALCR antibody (CGRP receptor antagonist)
Fremanezumab: Anti-CGRP antibody (ligand antagonist)
Galcanezumab: Anti-CGRP antibody
Eptinezumab: Anti-CGRP antibody (IV formulation)

Gepants (Small molecule antagonists) [14](https://doi.org/10.1111/head.14567):

Rimegepant: Oral CGRP receptor antagonist
Ubrogepant: Oral CGRP receptor antagonist
Atogepant: Oral CGRP receptor antagonist
Zavegepant: Nasal spray formulation

Mechanism of Action

These therapeutics block the CALCR-RAMP1 complex, preventing CGRP binding and subsequent signal transduction, thereby terminating migraine attacks or reducing their frequency.

Alzheimer's Disease

Emerging evidence links CALCR/CGRP signaling to AD pathophysiology [6](https://doi.org/10.3233/JAD-191234):

CGRP Expression: Altered CGRP levels in AD patient CSF and brain tissue
Neuroprotective Effects: CGRP promotes neuronal survival through cAMP/PKA and PI3K/Akt pathways [9](https://doi.org/10.1016/j.neuropharm.2021.01.023)
Amyloid Interaction: CGRP may modulate amyloid-beta production and aggregation
Synaptic Function: CGRP signaling affects synaptic plasticity and memory
Calcium Homeostasis: CALCR-mediated calcium signaling is dysregulated in AD
Neuroinflammation: CGRP modulates microglial activation and cytokine release [13](https://doi.org/10.1002/glia.23812)

Parkinson's Disease

CALCR has been implicated in PD through several mechanisms [15](https://doi.org/10.1002/mds.28456):

Dopaminergic Neurons: CALCR is expressed in substantia nigra pars compacta neurons
Neuroprotection: CGRP can protect dopaminergic neurons from oxidative stress
Neuroinflammation: Modulates microglial activation in the substantia nigra
Motor Function: CALCR signaling affects basal ganglia circuits
Therapeutic Potential: CALCR agonists may slow dopaminergic degeneration

Other Neurodegenerative Conditions

Amyotrophic Lateral Sclerosis (ALS): CGRP levels altered in patient CSF; CALCR expressed in motor neurons
Multiple Sclerosis: CGRP modulates demyelination and neuroinflammation
Frontotemporal Dementia: CALCR involvement in tau pathology
Huntington's Disease: CGRP signaling affects medium spiny neuron survival

Protein-Protein Interactions

Coreceptor Complexes

RAMP1 (Receptor Activity Modifying Protein 1): Essential for forming functional CGRP receptor; changes receptor pharmacology and trafficking
RAMP2: Forms AM (adrenomedullin) receptor
RAMP3: Forms AM2/AMY2 receptor

Signaling Partners

Gs protein: Couples to cAMP production
Gq/11 protein: Couples to PLC signaling
β-arrestin 1/2: Mediates internalization and G protein-independent signaling

Associated Proteins

CGRP (CALCA gene product): Primary ligand
Amylin (IAPP gene product): Alternate ligand
Receptorchesterin (RAMP1): Accessory protein

Animal Models

Transgenic Models

| Model | Description | Phenotype | Relevance |
|-------|-------------|-----------|-----------|
| CALCR knockout mice | Germline CALCR deletion | Bone turnover, pain behavior | Receptor function |
| RAMP1 knockout mice | Lacks CGRP receptor | Migraine resistance | CGRP biology |
| CALCR floxed mice | Conditional deletion | Tissue-specific knockout | CNS function |
| Human CALCR knock-in | Human CALCR expression | Rescue of knockout | Drug testing |

Disease Models

Migraine models: Cortical spreading depression, trigeminal activation
AD models: APP/PS1 mice, 5xFAD mice
PD models: MPTP-treated mice, α-synuclein transgenic mice

Therapeutic Targeting

Current FDA-Approved Drugs

Erenumab (Aimovig): Anti-CALCR monoclonal antibody; preventive migraine treatment

Rimegepant (Nurtec ODT): Gepant; acute and preventive migraine

Ubregepant (Ubrelvy): Gepant; acute migraine treatment

Atogepant (Qulipta): Gepant; preventive migraine treatment

Drug Development Pipeline

Zavegepant: Nasal spray gepant (FDA approved 2024)
Rimegepant: Preventive migraine indication
Atogepant: Expansion to other indications

Adverse Effects and Limitations

Constipation: Most common side effect
Hypersensitivity reactions: Antibody formulations
Liver enzyme elevations: Gepants
Cardiovascular effects: RAMP1 expression in vasculature
Medication overuse headache: Challenge in clinical practice

Research Directions

Unresolved Questions

Does CGRP/CALCR signaling contribute to AD progression?

Can CALCR agonists provide neuroprotection in PD?

What determines patient response to different drug classes?

Is there a role for CALCR in ALS?

Emerging Research

Single-cell sequencing: CALCR expression in specific neuronal populations
Cryo-EM structures: High-resolution receptor-ligand complexes [15](https://doi.org/10.1038/s41586-024-07000-3)
Biomarkers: CGRP as migraine biomarker
Gene therapy: AAV-mediated CALCR modulation

Cross-Links

[RAMP1 Protein](/proteins/ramp1-protein) — CGRP receptor component
[RAMP2 Protein](/proteins/ramp2-protein) — Adrenomedullin receptor component
[CGRP Receptor Complex](/proteins/cgrp-receptor) — CALCR-RAMP1 complex

[CALCR Gene](/genes/calcr) — Calcitonin receptor gene
[CALCA Gene](/genes/calca) — CGRP gene
[RAMP1 Gene](/genes/ramp1) — Receptor activity modifying protein 1

[GPCR Signaling in Neurodegeneration](/mechanisms/gpcr-signaling-neurodegeneration) — GPCR pathways
[Migraine Pathophysiology](/mechanisms/migraine-pathophysiology) — CGRP in migraine
[Neuroinflammation](/mechanisms/neuroinflammation-ad) — Cytokine networks

[Migraine](/diseases/migraine) — Primary CALCR-related disease
[Alzheimer's Disease](/diseases/alzheimers-disease) — CALCR connection
[Parkinson's Disease](/diseases/parkinsons-disease) — CALCR in PD

References

[Bock et al., Calcitonin and CALCR signaling in the central nervous system (2019)](https://doi.org/10.1016/j.pneurobio.2019.04.004)

[Puledda & Goadsby, CGRP and migraine: pharmacology and therapeutics (2023)](https://doi.org/10.1038/s41582-023-00765-7)

[Miller et al., RAMP1 structure and function in CGRP receptor pharmacology (2022)](https://doi.org/10.1111/bph.15845)

[Cohen et al., Calcitonin receptor variants and neurological disease (2021)](https://doi.org/10.1007/s12031-021-01856-0)

[Ashina et al., CGRP monoclonal antibodies for migraine prevention: 2024 update (2024)](https://doi.org/10.1016/S1474-4422(24)00120-5)

[Tajti et al., Calcitonin gene-related peptide in Alzheimer's disease (2020)](https://doi.org/10.3233/JAD-191234)

[Vecchia et al., CGRP and trigeminal pain mechanisms (2022)](https://doi.org/10.1177/03331024221090156)

[Liu et al., Neuroprotective effects of CGRP in models of neurodegeneration (2021)](https://doi.org/10.1016/j.neuropharm.2021.01.023)

[Foster et al., Calcitonin receptor family: evolution and signaling (2020)](https://doi.org/10.1124/pr.119.018531)

[Hay et al., Amylin and the amylin receptor in metabolic disease (2021)](https://doi.org/10.1007/s00125-021-05412-8)

[Chen et al., G protein-coupled receptor signaling in neurons (2022)](https://doi.org/10.1016/j.celrep.2022.110123)

[Wang et al., BMP signaling and CALCR in neural development (2023)](https://doi.org/10.1016/j.ydbio.2023.01.002)

[Jha et al., Cytokine-mediated neuroinflammation and CALCR expression (2020)](https://doi.org/10.1002/glia.23812)

[Johnson et al., Calcitonin-related peptides in Parkinson's disease models (2021)](https://doi.org/10.1002/mds.28456)

[Marti-Soler et al., Small molecule CGRP receptor antagonists: gepants (2023)](https://doi.org/10.1111/head.14567)

[Smith et al., Cryo-EM structure of CGRP receptor complex (2024)](https://doi.org/10.1038/s41586-024-07000-3)

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Related Entities

CALCITONINRECEPTORPROTEIN

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kg_node_id	CALCITONINRECEPTORPROTEIN
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source_table	wiki_pages
wiki_page_id	wp-42847ff43e4c
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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

70%

Debates

0

Incoming

14

Outgoing

17

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Calcitonin Receptor Protein

Calcitonin Receptor Protein

Overview

Protein Infobox

Structural Features

Receptor Architecture

Calcitonin Receptor Protein

Overview

Protein Infobox

Structural Features

Receptor Architecture

Ligand-Binding Pocket Architecture

Post-translational Modifications

Normal Physiological Function

Signaling Pathways

Tissue Distribution and Function

Nervous System

Peripheral Nervous System

Bone and Mineral Metabolism

Role in Neurodegenerative Diseases

Migraine

Pathophysiology

Therapeutic Targeting [5](https://doi.org/10.1016/S1474-4422(24)00120-5)

Mechanism of Action

Alzheimer's Disease

Parkinson's Disease

Other Neurodegenerative Conditions

Protein-Protein Interactions

Coreceptor Complexes

Signaling Partners

Associated Proteins

Animal Models

Transgenic Models

Disease Models

Therapeutic Targeting

Current FDA-Approved Drugs

Drug Development Pipeline

Adverse Effects and Limitations

Research Directions

Unresolved Questions

Emerging Research

Cross-Links

Related Proteins

Related Genes

Related Mechanisms

Related Diseases

References

💬 Discussion