ADRA2 - Alpha-2A(2B) (2C) Adrenergic receptor | Elisa - Clia - Antibody - Protein

Background

The alpha-2 adrenergic receptors (ADRA2) are a class of G protein-coupled receptors (GPCRs) that respond to the neurotransmitter noradrenaline (norepinephrine) and play a role in regulating various physiological processes. There are three main subtypes of alpha-2 adrenergic receptors: Alpha-2A (ADRA2A), Alpha-2B (ADRA2B), and Alpha-2C (ADRA2C). ADRA2A receptors are primarily located in the central nervous system, including the brain and spinal cord. They are involved in the modulation of neurotransmitter release, particularly in the regulation of noradrenaline release. Activation of ADRA2A receptors inhibits the release of neurotransmitters such as noradrenaline, dopamine, and serotonin, leading to a decrease in sympathetic nervous system activity. ADRA2A receptors also play a role in regulating blood pressure, cognition, and mood. ADRA2B receptors are found in various tissues, including vascular smooth muscle, the heart, and the pancreas. They are involved in the regulation of vascular tone, cardiac function, and insulin secretion. Activation of ADRA2B receptors leads to vasoconstriction, decreased heart rate, and inhibition of insulin release from pancreatic beta cells. ADRA2B receptors also play a role in modulating neurotransmitter release in the central nervous system.ADRA2C receptors are widely distributed in the central nervous system, as well as in peripheral tissues such as vascular smooth muscle and the heart. They play a role in regulating sympathetic nervous system activity, vascular tone, and cardiac function. Activation of ADRA2C receptors leads to vasoconstriction and decreased heart rate. ADRA2C receptors also modulate neurotransmitter release in the central nervous system.

Protein Structure

The α2-adrenergic receptors share a common GPCR structure:

• Seven Transmembrane Domains: Typical of GPCRs, these domains span the cell membrane.
• Extracellular N-terminus: Involved in ligand binding.
• Intracellular C-terminus: Participates in signaling and interactions with G proteins and other intracellular molecules.
• Ligand Binding Site: Located within the transmembrane regions.

Classification and Subtypes

The ADRA2 family consists of three subtypes based on their gene encoding and tissue distribution:

• ADRA2A: Encodes the α2A-adrenergic receptor, primarily found in the central nervous system (CNS), platelets, and various tissues involved in autonomic functions.
• ADRA2B: Encodes the α2B-adrenergic receptor, predominantly expressed in the vascular smooth muscle and some central nervous system regions.
• ADRA2C: Encodes the α2C-adrenergic receptor, mainly located in the CNS and some peripheral tissues.

Function and Biological Significance

Alpha-2 adrenergic receptors mediate various physiological responses by inhibiting adenylate cyclase activity through interaction with Gi/o proteins, leading to decreased cyclic AMP (cAMP) levels:

1. Inhibition of Neurotransmitter Release: α2-ARs inhibit the release of norepinephrine and other neurotransmitters, providing a feedback mechanism to regulate sympathetic activity.
2. Vasoconstriction: These receptors induce vasoconstriction in vascular smooth muscle, contributing to the regulation of blood pressure.
3. Sedation and Analgesia: Activation of α2-ARs in the CNS leads to sedative and analgesic effects.
4. Metabolic Effects: α2-ARs are involved in regulating insulin release and lipolysis.

Interactions

1. Gi/o Proteins: Upon activation, α2-ARs interact with Gi/o proteins, leading to the inhibition of adenylate cyclase and a decrease in cAMP levels.
2. Adenylate Cyclase: Inhibition of this enzyme results in reduced cAMP production, affecting various downstream signaling pathways.
3. Ion Channels: α2-ARs can modulate ion channels, including calcium and potassium channels, influencing cellular excitability and neurotransmitter release.

Clinical Significance

1. Hypertension: Alpha-2 agonists, such as clonidine, are used to treat hypertension by reducing sympathetic outflow and lowering blood pressure.
2. Anxiety and Sedation: α2-AR agonists are used for their sedative and anxiolytic effects in clinical settings, particularly in anesthesia.
3. Chronic Pain Management: Activation of α2-ARs provides analgesic effects, making these receptors targets for pain management.
4. Attention Deficit Hyperactivity Disorder (ADHD): Drugs targeting α2-ARs, such as guanfacine, are used in the treatment of ADHD due to their calming and focus-enhancing effects.
5. Opiate Withdrawal: α2-AR agonists help manage symptoms of opiate withdrawal by reducing sympathetic overactivity.

Summary

Alpha-2 adrenergic receptors (α2-ARs), including subtypes α2A, α2B, and α2C, are GPCRs that play a crucial role in regulating neurotransmitter release, vasoconstriction, sedation, analgesia, and metabolic processes. They inhibit adenylate cyclase activity through interaction with Gi/o proteins, leading to decreased cAMP levels. Clinically, α2-ARs are significant in managing hypertension, anxiety, sedation, chronic pain, ADHD, and opiate withdrawal. Understanding the roles and mechanisms of α2-ARs is essential for developing therapeutic strategies targeting these receptors.