Adrenergic Transmission Overview

Adrenergic Transmission

• Synthesis of Noradrenaline (NA): Begins with tyrosine, converted through several steps involving enzymes like tyrosine hydroxylase, DOPA decarboxylase, and dopamine hydroxylase.
• Adrenaline Synthesis: NA is further converted to adrenaline by phenylethanolamine N-methyl transferase enzyme, primarily in the adrenal medulla.

Storage and Release of Noradrenaline

• NA is stored with ATP in presynaptic vesicles.
• Release: Triggered by calcium influx via voltage-gated calcium channels, leading to exocytosis.
• Non-exocytotic Release: Certain drugs like amphetamine can displace and release NE from vesicles.

Regulation of Noradrenaline Release

• Auto-inhibitory Feedback Mechanism: Release of NA stimulates α2 receptors in the presynaptic neuron, inhibiting further release.

Elimination of Catecholamines

• Reuptake:
  • Uptake 1 (presynaptic): More selective for NA.
  • Uptake 2 (extraneuronal): Occurs in effector organs like the heart and smooth muscle; more selective for adrenaline.
• Metabolism:
  • Monoamine Oxidase (MAO): Found in mitochondria, primarily in neurons.
  • Catechol-O-Methyl Transferase (COMT): Found in various neuronal and non-neuronal tissues.

Classification of Adrenoceptors

• Divided into two main classes:
  • α receptors: (α1 and α2)
  • β receptors: (β1, β2, and β3)

Actions of Adrenergic Receptors

• α1 Receptors:
  • Found in smooth muscle of various organs, causing contraction of blood vessels.
  • Relaxation of the gastrointestinal tract (GIT).
  • Contraction of all sphincters (GIT, urinary).
  • Mydriasis (dilation of pupil) due to contraction of the dilator pupillae muscle.
• α2 Receptors:
  • Found in presynaptic neurons, CNS, and blood vessels.
  • Inhibit neurotransmitter release.
  • Promote platelet aggregation.
  • When postsynaptically, they can function similar to α1 receptors.
• β1 Receptors:
  • Primarily found in the heart, increasing contractility and heart rate upon stimulation.
• β2 Receptors:
  • Present in smooth muscle, leading to bronchodilation, peripheral vasodilation, relaxation of visceral smooth muscle, and skeletal muscle tremor.
  • Increase aqueous humor secretion.
  • Increase liver glycogenolysis.
• β3 Receptors:
  • Role in lipolysis and thermogenesis.

Adrenergic Receptor Agonist Potency

• Adrenaline, noradrenaline, and isoprenaline act on both α and β receptors with varying potencies.
  • Noradrenaline more strongly stimulates α receptors.
  • Isoprenaline more strongly stimulates β receptors.

Acetylcholine (ACh) Synthesis

• Choline Uptake: Transported from extracellular fluid into the cytoplasm of cholinergic neurons by an energy-dependent carrier system.
• Acetylcholine Synthesis: Choline acetyltransferase catalyzes the reaction of choline with acetyl CoA to form acetylcholine.

Storage of Acetylcholine

• Packaged into presynaptic vesicles via active transport.
• Mature vesicles contain ACh, ATP, and proteoglycans.
• Vesamicol blocks the uptake of ACh into synaptic vesicles.

Release of Acetylcholine

• Action potential arrival at the nerve terminal opens voltage-gated calcium channels, increasing intracellular calcium concentration.
• This triggers fusion of vesicles with the cell membrane, releasing their contents into the synaptic space.
• Botulinum toxin: Blocks the release of ACh.

Degradation and Recycling of Acetylcholine

• Degradation: Acetylcholinesterase (AChE) cleaves ACh into choline and acetate in the synaptic cleft.
• Recycling: Choline is recaptured by a high-affinity uptake system, transported back into the neuron, and used for the synthesis of new acetylcholine.

Acetylcholine Receptors

• Two major classes of receptors in the parasympathetic system:
  • Nicotinic receptors:
  • Muscarinic receptors: