Alpha-2C Adrenergic Receptor Protein

Alpha-2C Adrenergic Receptor (α2C-AR) Protein

Introduction

Alpha 2C Adrenergic Receptor Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-protein"> [@macdonald1997]
<table> [@kable2000]
<tr><th colspan="2" style="background:#4477AA; color:white; text-align:center">ADRA2C</th></tr> [@hunter1997]
<tr><th>Protein Name</th><td>Alpha-2C Adrenergic Receptor</td></tr> [@gilsbach2012]
<tr><th>Gene</th><td>[ADRA2C](/genes/adra2c)</td></tr>
<tr><th>UniProt ID</th><td>[P43681](https://www.uniprot.org/uniprot/P43681)</td></tr>
<tr><th>PDB IDs</th><td>5E94, 6GKY</td></tr>
<tr><th>Molecular Weight</th><td>50.3 kDa</td></tr>
<tr><th>Subcellular Localization</th><td>Plasma Membrane</td></tr>
<tr><th>Protein Family</th><td>GPCR, Class A, Adrenergic</td></tr>
</table>
</div>

Overview

The alpha-2C adrenergic receptor (α2C-AR), encoded by the ADRA2C gene, is a G protein-coupled receptor (GPCR) that mediates the inhibitory effects of norepinephrine and epinephrine. It is widely expressed in the central nervous system and peripheral tissues, where it plays crucial roles in modulating autonomic function, mood, and cognitive processes.

Structure

...

Alpha-2C Adrenergic Receptor (α2C-AR) Protein

Introduction

Alpha 2C Adrenergic Receptor Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-protein"> [@macdonald1997]
<table> [@kable2000]
<tr><th colspan="2" style="background:#4477AA; color:white; text-align:center">ADRA2C</th></tr> [@hunter1997]
<tr><th>Protein Name</th><td>Alpha-2C Adrenergic Receptor</td></tr> [@gilsbach2012]
<tr><th>Gene</th><td>[ADRA2C](/genes/adra2c)</td></tr>
<tr><th>UniProt ID</th><td>[P43681](https://www.uniprot.org/uniprot/P43681)</td></tr>
<tr><th>PDB IDs</th><td>5E94, 6GKY</td></tr>
<tr><th>Molecular Weight</th><td>50.3 kDa</td></tr>
<tr><th>Subcellular Localization</th><td>Plasma Membrane</td></tr>
<tr><th>Protein Family</th><td>GPCR, Class A, Adrenergic</td></tr>
</table>
</div>

Overview

The alpha-2C adrenergic receptor (α2C-AR), encoded by the ADRA2C gene, is a G protein-coupled receptor (GPCR) that mediates the inhibitory effects of norepinephrine and epinephrine. It is widely expressed in the central nervous system and peripheral tissues, where it plays crucial roles in modulating autonomic function, mood, and cognitive processes.

Structure

α2C-AR has characteristic GPCR architecture:

• N-terminal Extracellular Domain: Contains glycosylation sites
• Seven Transmembrane Domains: α-helices forming the ligand-binding pocket
• Three Extracellular Loops: Involved in ligand recognition
• Three Intracellular Loops: Couple to G proteins
• C-terminal Intracellular Tail: Contains phosphorylation sites for desensitization

Key structural features:

• Conserved DRY motif for G protein coupling
• Serine/threonine residues in C-tail for phosphorylation
• Disulfide bond between extracellular loops

Normal Function

Gi/o Protein Coupling

• Activates Gi/o proteins upon ligand binding
• Inhibits adenylate cyclase, reducing cAMP production
• Activates G protein-gated inward rectifier potassium channels (GIRKs)

Neuronal Effects

• Hyperpolarizes [neurons](/entities/neurons) through GIRK activation
• Reduces neurotransmitter release (presynaptic inhibition)
• Modulates neuronal excitability

Physiological Roles

• Thermoregulation: Brown adipose tissue thermogenesis
• Pain Modulation: Spinal cord analgesic pathways
• Mood and Arousal: Limbic system modulation
• Metabolism: Lipolysis and insulin secretion regulation

Expression Pattern

α2C-AR distribution in the brain and body:

• Central Nervous System:
• [Hippocampus](/brain-regions/hippocampus) (CA1-CA3 regions)
• Cerebral [cortex](/brain-regions/cortex) (layers I-VI)
• Amygdala (basolateral and central nuclei)
• Hypothalamus (preoptic area, arcuate nucleus)
• Locus coeruleus (autoreceptors)
• Spinal cord (dorsal horn)
• Peripheral Tissues:
• Adipose tissue (brown and white)
• Platelets
• Pancreas (beta cells)
• Kidney

Role in Neurodegeneration

α2C-AR is implicated in neurodegenerative diseases:

Alzheimer's Disease

• Dysregulated norepinephrine signaling affects amyloid processing
• Altered receptor expression in AD brains
• Potential for cognitive enhancement with targeted agonists

Parkinson's Disease

• Altered adrenergic modulation in substantia nigra
• Contributes to non-motor symptoms
• Potential therapeutic target for dyskinesias

Stroke/Ischemia

• Neuroprotective effects of α2-adrenergic agonists
• Reduced infarct size in experimental models

Chronic Pain

• Spinal α2C-AR involvement in analgesic pathways
• Target for novel analgesic development

Therapeutic Implications

Drug Targets

• Agonists: Clonidine, guanfacine, dexmedetomidine
• Antagonists: Yohimbine, atipamezole

Clinical Applications

• Hypertension: Central α2 agonists (clonidine, guanfacine)
• ADHD: Guanfacine (Intuniv) for attention enhancement
• Opioid Withdrawal: Clonidine for detoxification
• Sedation: Dexmedetomidine in ICU sedation
• Pain: Spinal α2-AR modulation

Neurodegeneration

• Cognitive enhancement potential
• Neuroprotection in stroke
• Modulation of neuroinflammation

Research Directions

Development of subtype-selective α2C-AR ligands

Understanding CNS vs. peripheral distribution for drug design

Gene therapy approaches for α2C-AR dysregulation

Biomarker development for receptor activity

Background

The study of Alpha 2C Adrenergic Receptor Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

See Also

• Alpha-2C Adrenergic Receptor Gene - Gene page
• Adrenergic Receptors - Category
• [Parkinson's Disease](/diseases/parkinsons- [Alzheimer's Disease](/diseases/alzheimers-disease)isease
• [Alzheimer's Disease](/diseases/alzheimers-disease) Alzheimer's disease

External Links

• [UniProt: P08913](https://www.uniprot.org/uniprot/P08913) - ADRA2C protein entry
• [IUPHAR: Alpha-2C](https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=76) - Receptor pharmacology

References

[Unknown, Limbird LE (2004). Receptors linked to inhibition of adenylate cyclase (2004)](https://pubmed.ncbi.nlm.nih.gov/14977411/)

[Macdonald K, et al, (1997) (1997)](https://pubmed.ncbi.nlm.nih.gov/9037624/)

[Kable JW, et al, (2000) (2000)](https://pubmed.ncbi.nlm.nih.gov/10683723/)

[Hunter JC, et al, (1997) (1997)](https://pubmed.ncbi.nlm.nih.gov/9037617/)

[Gilsbach R, et al, (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22790197/)