Acetylecholine and adrenaline

 

Acetylcholine (ACh)

Overview: Acetylcholine (ACh) is a neurotransmitter that plays a crucial role in the nervous system, especially in the autonomic nervous system (ANS) and the somatic nervous system (SNS). It was the first neurotransmitter to be discovered and is involved in various physiological functions.

Synthesis: Acetylcholine is synthesized in the nerve terminal from two precursors:

• Choline (from diet or synthesized in the liver)
• Acetyl-CoA (produced in the mitochondria)

The enzyme choline acetyltransferase (ChAT) catalyzes the reaction to produce acetylcholine from acetyl-CoA and choline.

Release: Acetylcholine is stored in vesicles at the nerve terminals. Upon the arrival of an action potential, calcium ions (Ca²⁺) enter the presynaptic neuron, prompting the vesicles to fuse with the membrane and release ACh into the synaptic cleft via exocytosis.

Receptors: Acetylcholine acts on two types of receptors:

1. Nicotinic Receptors (nAChRs): These are ionotropic receptors, primarily located at neuromuscular junctions, autonomic ganglia, and in the CNS. They are responsible for fast synaptic transmission.
2. Muscarinic Receptors (mAChRs): These are G-protein coupled receptors (GPCRs), located in the parasympathetic nervous system and in various parts of the CNS. They mediate slower, prolonged responses.

Functions:

• Somatic Nervous System: In the neuromuscular junction, ACh binds to nicotinic receptors, causing muscle contraction.
• Autonomic Nervous System: In the parasympathetic division, ACh acts on muscarinic receptors to mediate "rest and digest" activities such as:
  • Reducing heart rate (via M2 receptors on the heart)
  • Stimulating gastrointestinal activity (via M3 receptors in the GI tract)
  • Stimulating secretions, like saliva and sweat
• Central Nervous System (CNS): ACh is involved in arousal, attention, memory, and motivation. Reduced levels of ACh are implicated in neurodegenerative diseases such as Alzheimer's disease.

Termination of Action: After binding to its receptors, ACh is quickly broken down in the synaptic cleft by the enzyme acetylcholinesterase (AChE) into choline and acetate. Choline is then recycled back into the presynaptic neuron for reuse.

Clinical Relevance:

• Alzheimer’s Disease: Decreased levels of acetylcholine are observed in patients, and some treatments aim to enhance cholinergic activity.
• Myasthenia Gravis: This is an autoimmune disease where antibodies block or destroy nicotinic receptors at the neuromuscular junction, leading to muscle weakness.
• Botulinum Toxin (Botox): This toxin inhibits the release of acetylcholine, preventing muscle contraction, which is why it is used cosmetically to reduce wrinkles and clinically to treat muscle spasticity.

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Adrenaline (Epinephrine)

Overview: Adrenaline, also known as epinephrine, is both a hormone and a neurotransmitter. It is synthesized in the adrenal medulla and plays a critical role in the body's response to stress (the "fight-or-flight" response) by increasing the availability of resources (e.g., glucose, oxygen) needed to respond to threats.

Synthesis: Adrenaline is synthesized from tyrosine, an amino acid. The steps involved are:

1. Tyrosine is converted to L-DOPA by the enzyme tyrosine hydroxylase.
2. L-DOPA is converted to dopamine.
3. Dopamine is converted to norepinephrine.
4. Norepinephrine is converted to adrenaline by the enzyme phenylethanolamine N-methyltransferase (PNMT), which adds a methyl group.

Release: Adrenaline is released primarily from the adrenal medulla into the bloodstream in response to activation of the sympathetic nervous system. Stress, fear, excitement, and physical exertion can trigger this release. Once in the bloodstream, it acts on target organs.

Receptors: Adrenaline binds to adrenergic receptors, which are G-protein-coupled receptors:

1. Alpha receptors (α₁, α₂): Mediate vasoconstriction, increased peripheral resistance, and pupil dilation.
2. Beta receptors (β₁, β₂, β₃): Mediate increased heart rate, bronchodilation, and lipolysis.
   • β₁ receptors: Found primarily in the heart, where they increase heart rate and contractility.
   • β₂ receptors: Found in smooth muscles of the bronchi, leading to bronchodilation, and in blood vessels, causing vasodilation.
   • β₃ receptors: Primarily involved in adipose tissue regulation and stimulate lipolysis.

Functions: Adrenaline has a widespread effect on various organ systems:

• Cardiovascular System: Increases heart rate (chronotropic effect) and the force of heart contraction (inotropic effect), raising blood pressure.
• Respiratory System: Causes bronchodilation, improving airflow and oxygen uptake.
• Metabolic Effects: Increases blood glucose levels by promoting glycogenolysis (breakdown of glycogen into glucose) and gluconeogenesis in the liver, and stimulates lipolysis (fat breakdown) in adipose tissue.
• Skeletal Muscles: Enhances blood flow to skeletal muscles, preparing them for activity.
• Pupils: Causes dilation of the pupils (mydriasis), increasing light entry into the eyes.

Fight-or-Flight Response: In a stress response:

1. Adrenaline increases blood flow to essential organs (heart, lungs, muscles) and reduces it to non-essential organs (skin, digestive system).
2. It mobilizes energy reserves by increasing glucose and fatty acids in the bloodstream.
3. Adrenaline reduces non-essential functions like digestion and stimulates key processes like alertness and readiness for physical exertion.

Termination of Action: Adrenaline’s effects are terminated when it is taken back into nerve terminals, broken down by enzymes such as monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), or diffuses away from the synaptic or receptor site.

Clinical Relevance:

• Anaphylaxis: Adrenaline is used as an emergency treatment for anaphylactic shock, as it counteracts severe allergic reactions by relaxing airways and tightening blood vessels.
• Asthma: Adrenaline’s bronchodilator effects are leveraged in some emergency asthma treatments.
• Cardiac Arrest: Adrenaline is often used in advanced cardiac life support (ACLS) to stimulate heart function in patients experiencing cardiac arrest.
• Adrenergic Agonists: Drugs that mimic the effects of adrenaline are used in conditions like hypotension, shock, and asthma.