CASR Gene

CASR Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CASR — Calcium-Sensing Receptor</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>CASR</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Calcium-Sensing Receptor</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>3q21.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/846" target="_blank">846</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000036828" target="_blank">ENSG00000036828</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/601199" target="_blank">601199</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9UII2" target="_blank">Q9UII2</a></td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>GPCR (Class C), Metabotrophic glutamate receptor family</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Brain (cerebellum, hippocampus, cortex), Parathyroid, Kidney, Pancreas</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">Parkinson</a>, <a href="/wiki/parkinson's-disease" style="color:#ef9a9a">Parkinson's Disease</a></td>
</tr>
<tr>
<td cl

CASR Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CASR — Calcium-Sensing Receptor</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>CASR</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Calcium-Sensing Receptor</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>3q21.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/846" target="_blank">846</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000036828" target="_blank">ENSG00000036828</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/601199" target="_blank">601199</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9UII2" target="_blank">Q9UII2</a></td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>GPCR (Class C), Metabotrophic glutamate receptor family</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Brain (cerebellum, hippocampus, cortex), Parathyroid, Kidney, Pancreas</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">Parkinson</a>, <a href="/wiki/parkinson's-disease" style="color:#ef9a9a">Parkinson's Disease</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">13 edges</a></td>
</tr>
</table>

CASR — Calcium-Sensing Receptor

Overview

The Calcium-Sensing Receptor (CASR) is a class C G protein-coupled receptor that functions as the principal sensor of extracellular calcium concentrations in the body. Originally characterized for its critical role in calcium homeostasis in parathyroid and kidney, CASR is now recognized as having significant functions in the central nervous system (CNS), where it participates in synaptic plasticity, neuronal excitability, and cellular responses to pathological stimuli["@caspi2012"].

CASR belongs to the metabotropic glutamate receptor family, which includes eight members (mGluR1-8) and the GABA["B"] receptors. These receptors share a common architecture with a large extracellular venus flytrap (VFT) domain, a cysteine-rich domain, and a seven transmembrane domain. Unlike the ionotropic glutamate receptors that function as ligand-gated ion channels, metabotropic receptors modulate synaptic transmission through G protein-mediated signaling cascades.

Gene Structure and Evolution

The human CASR gene spans approximately 73 kb on chromosome 3q21.1 and comprises 11 exons. The coding sequence is highly conserved across mammals, reflecting the critical nature of calcium sensing in vertebrate physiology. The promoter region contains multiple transcription factor binding sites, allowing for tissue-specific expression and regulation by various hormonal and developmental signals.

Alternative splicing generates multiple CASR variants with different tissue distributions and functional properties. The most common splice variants differ in their C-terminal tail length, which affects receptor desensitization and trafficking. In the brain, specific splice variants are enriched in different neuronal populations, suggesting specialized functions in distinct brain regions.

Protein Structure and Function

Extracellular Domain

The extracellular Venus flytrap (VFT) domain of CASR contains the calcium binding sites. Each receptor monomer has multiple calcium binding pockets within the VFT, with calcium ions coordinating to negatively charged amino acid residues. The binding of calcium induces conformational changes that transmit across the receptor to the intracellular domains.

The VFT domain also contains binding sites for various allosteric modulators, including L-amino acids (particularly aromatic and aliphatic amino acids), which potentiate calcium-induced receptor activation. This amino acid sensing function may have relevance to neuronal metabolism and stress responses.

Transmembrane Domain

The seven transmembrane helices form the canonical GPCR transmembrane bundle. The transmembrane domains contain binding sites for positive and negative allosteric modulators, including calcimimetics (e.g., cinacalcet) used clinically for treating secondary hyperparathyroidism, and calcilytics that act as receptor antagonists.

Intracellular Domain and Signaling

The intracellular C-terminal tail contains multiple serine and threonine residues that can be phosphorylated, as well as motifs for interaction with scaffolding proteins and downstream signaling molecules. CASR signals primarily through:

• Gq/11 family G proteins: Activating phospholipase C (PLC), leading to inositol trisphosphate (IP3) and diacylglycerol (DAG) production
• Gi/o family G proteins: Inhibiting adenylate cyclase and reducing cAMP levels
• G12/13 family G proteins: Activating Rho GTPase pathways affecting cytoskeletal dynamics

Expression in the Brain

Regional Distribution

CASR is expressed throughout the central nervous system with particularly high levels in:

• Hippocampus: CA1-CA3 regions, dentate gyrus — areas critical for learning and memory
• Cerebellum: Purkinje cells and granule cell layer — motor coordination
• Cerebral cortex: Layer V pyramidal neurons — executive function
• Hypothalamus: Paraventricular and supraoptic nuclei — autonomic regulation
• Substantia nigra: Dopaminergic neurons — motor control
• Brainstem: Nucleus tractus solitarius — sensory processing

Cellular Localization

At the cellular level, CASR localizes to:

• Synaptic terminals: Both presynaptic and postsynaptic compartments
• Dendritic shafts: Along dendritic trunks and branches
• Somatic membrane: Cell body plasma membrane
• Endoplasmic reticulum: Intracellular calcium stores
• Growth cones: During neuronal development

Physiological Functions in the Brain

Calcium Homeostasis at Synapses

In neurons, CASR participates in local calcium sensing at synapses. The extracellular calcium concentration at synaptic clefts changes during neuronal activity, with lower calcium during high-frequency firing. CASR may function as a sensor linking synaptic activity to adaptive responses.

Synaptic Plasticity

CASR activation modulates synaptic plasticity, the cellular basis for learning and memory. Studies have shown that:

• CASR activation can enhance long-term potentiation (LTP) in hippocampal neurons
• CASR antagonists impair memory consolidation in behavioral tasks
• CASR expression changes during age-related cognitive decline

Neuronal Excitability

By modulating voltage-gated calcium channels and potassium channels, CASR affects neuronal excitability. CASR activation generally reduces neuronal firing rate through activation of calcium-activated potassium channels. This may serve as a negative feedback mechanism preventing excessive neuronal activation.

Neuroprotection

Under various stress conditions, CASR activation can be neuroprotective:

• Oxidative stress: CASR signaling activates antioxidant pathways
• Excitotoxicity: CASR modulates glutamate receptor function
• Metabolic stress: CASR helps maintain cellular energy balance

Role in Alzheimer's Disease

Amyloid Processing

CASR has complex interactions with amyloid precursor protein (APP) processing and amyloid-beta (Aβ) metabolism. Several mechanisms have been proposed:

• APP trafficking: CASR signaling affects APP trafficking through the secretory and endosomal pathways
• Beta-secretase activity: CASR modulation of BACE1 expression and activity
• Aβ aggregation: CASR may directly interact with Aβ species

Tau Pathology

CASR signaling affects tau phosphorylation through multiple kinase pathways:

• GSK3β activation: CASR can activate glycogen synthase kinase 3 beta (GSK3β), a key kinase in tau phosphorylation
• CDK5 modulation: CASR affects cyclin-dependent kinase 5 (CDK5) activity
• PP2A regulation: CASR can modulate protein phosphatase 2A (PP2A), the major tau phosphatase

Synaptic Dysfunction

In Alzheimer's disease, CASR contributes to synaptic dysfunction through:

• NMDA receptor modulation: Alters NMDA receptor trafficking and function
• Dendritic spine loss: Affects actin cytoskeleton dynamics
• Calcium dysregulation: Contributes to calcium homeostasis failure

Neuroinflammation

CASR plays a significant role in neuroinflammation, a key feature of AD pathogenesis:

• Microglial activation: CASR on microglia senses pathological calcium changes
• Cytokine production: CASR signaling modulates inflammatory cytokine release
• NLRP3 inflammasome: CASR contributes to inflammasome activation

Role in Parkinson's Disease

Dopaminergic Neuron Survival

In the substantia nigra, CASR is expressed in dopaminergic neurons and affects their survival:

• Mitochondrial function: CASR signaling modulates mitochondrial calcium handling
• Oxidative stress: CASR activation can induce antioxidant responses
• Apoptosis: CASR can be protective against apoptotic stimuli

Alpha-Synuclein Aggregation

CASR may influence alpha-synuclein (α-syn) aggregation through:

• Protein folding: CASR-mediated calcium changes affect protein folding quality control
• Aggregation kinetics: Calcium can promote α-syn aggregation
• Autophagy modulation: CASR affects autophagy pathways that clear aggregated proteins

Neuroinflammation in PD

Similar to AD, neuroinflammation plays a key role in PD pathogenesis, and CASR participates in:

• Microglial activation: CNS immune cell responses
• Peripheral inflammation: CASR in peripheral immune cells may affect CNS inflammation
• Cytokine networks: Modulation of pro-inflammatory and anti-inflammatory cytokines

Role in Amyotrophic Lateral Sclerosis (ALS)

In ALS, CASR dysregulation has been observed in:

• Motor neuron vulnerability: Altered calcium sensing in vulnerable motor neurons
• Glial cells: CASR in astrocytes and microglia affects neuroinflammation
• Muscle: CASR in neuromuscular junctions may affect transmission

Therapeutic Implications

Calcimimetics

Calcimimetic compounds that allosterically activate CASR have been developed for clinical use in secondary hyperparathyroidism. These compounds may have neuroprotective effects by:

• Reducing parathyroid hormone (PTH) levels and associated secondary effects
• Direct effects on neuronal CASR signaling
• Modulation of systemic calcium homeostasis

Calcilytics

Calcilytic compounds that antagonize CASR have been explored for:

• Osteoporosis treatment (through PTH release)
• Potential modulation of neuronal excitability

Novel Therapeutic Strategies

Based on current understanding, several therapeutic approaches targeting CASR could be developed:

Biomarker Potential

CASR expression or function may serve as a biomarker for:

• Disease progression in AD and PD
• Therapeutic response to calcium-modulating drugs
• Neuronal injury and neurodegeneration

Research Challenges and Future Directions

Key Questions

Several fundamental questions about CASR in neurodegeneration remain:

Research Tools Needed

Advancing the field requires:

• Better animal models: Transgenic and conditional knockout models
• Imaging tools: Live-cell calcium imaging and functional imaging
• Cell-specific approaches: Cell-type-specific CASR manipulation
• Clinical biomarkers: Peripheral and CSF markers of CASR function

Summary

The Calcium-Sensing Receptor (CASR) is a G protein-coupled receptor with emerging importance in neurodegenerative diseases. Originally characterized for its role in systemic calcium homeostasis, CASR is now recognized as having significant functions in the brain, where it affects synaptic plasticity, neuronal excitability, and neuroprotection.

In Alzheimer's disease, CASR contributes to amyloid processing, tau pathology, synaptic dysfunction, and neuroinflammation. In Parkinson's disease, CASR affects dopaminergic neuron survival, alpha-synuclein aggregation, and neuroinflammation. These connections make CASR an interesting therapeutic target, though significant research is needed to develop brain-penetrant modulators and understand the precise mechanistic connections.

External Links

• [NCBI Gene: CASR](https://www.ncbi.nlm.nih.gov/gene/846)
• [UniProt: CASR](https://www.uniprot.org/uniprot/Q9UII2)
• [Ensembl: CASR](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000036828)
• [OMIM: CASR](https://omim.org/entry/601199)
• [HGNC: CASR](https://www.genenames.org/data/hgnc_data.php?hgnc_id=1514)

References

See Also

• [Aging and Rejuvenation Knowledge Gaps](/wiki/gaps-aging) — encodes
• [Aging and Rejuvenation Knowledge Gaps](/wiki/gaps-aging) — expressed_in
• [Genes](/wiki/genes) — regulates
• [Spinal Trigeminal Nucleus in Neurodegeneration](/wiki/cell-types-spinal-trigeminal-nucleus-neurodegeneration) — expressed_in

Pathway Diagram

The following diagram shows the key molecular relationships involving CASR Gene discovered through SciDEX knowledge graph analysis: