Transmission at the Post-Ganglionic Sympathetic Synapse ANS 4

  • Synthesis, Release, Uptake, and Metabolism of Noradrenaline:

    1. Synthesis Path: Noradrenaline (norepinephrine) is synthesized via a multi-step enzymatic pathway:

    • Tyrosine is transported into the nerve terminal.

    • Tyrosine Hydroxylase (TH): Converts Tyrosine to L-DOPA (The rate-limiting step).

    • DOPA Decarboxylase: Converts L-DOPA to Dopamine.

    • Dopamine beta-hydroxylase (DBH): Converts Dopamine to Noradrenaline within the synaptic vesicles.

    1. Storage and Release: Noradrenaline is sequestered into vesicles by the Vesicular Monoamine Transporter (VMAT). Release occurs via calcium-dependent exocytosis upon depolarization.

    2. Termination of Action:

    • Uptake 1 (Neuronal): Primary mechanism; reuptake into the presynaptic terminal via the Norepinephrine Transporter (NET).

    • Uptake 2 (Extraneuronal): Reuptake into non-neuronal cells.

    1. Metabolism: Enzymatic degradation involves Monoamine Oxidase (MAO) (mitochondrial) and Catechol-O-methyltransferase (COMT) (cytoplasmic/extracellular).

  • Classification and Signaling of Adrenergic Receptors:

  • Alpha Receptors:

    • alpha1: Linked to Gq proteins. Activates phospholipase C, increasing IP3 and DAG, leading to increased intracellular Ca^{2+}. Results in smooth muscle contraction (vasoconstriction).

    • alpha2: Linked to Gi proteins. Inhibits Adenylate Cyclase, decreasing cAMP. Often acts as presynaptic autoreceptors to inhibit further neurotransmitter release.

  • Beta Receptors: All linked to G_s proteins, activating Adenylate Cyclase and increasing cAMP.

    • beta_1: Primarily in the heart; increases heart rate (chronotropy) and force of contraction (inotropy).

    • beta_2: Primarily in bronchial smooth muscle and blood vessels of skeletal muscle; causes bronchodilation and vasodilation.

    • beta_3: Located in adipose tissue; mediates lipolysis.

Transmission at Cholinergic Synapses in the ANS

  • Synthesis and Release of Acetylcholine (ACh):

    • Synthesis: Choline is taken up by a high-affinity transporter and reacted with Acetyl-CoA by the enzyme Choline Acetyltransferase (ChAT).

    • Storage: ACh is transported into vesicles by the Vesicular Acetylcholine Transporter (VAChT).

    • Release: Triggered by Ca^{2+} influx through voltage-gated channels.

  • Receptor Classification:

    • Nicotinic Receptors (nAChR): Ligand-gated ion channels (Na^+, K^+, Ca^{2+}). Found at autonomic ganglia (NN subtype) and the neuromuscular junction (NM subtype).

    • Muscarinic Receptors (mAChR): G protein-coupled receptors (M1 through M5).

Dale's Experiment: The Dual Nature of ACh

  • Observation: Sir Henry Dale observed that ACh produced different cardiovascular responses depending on the dose and the presence of antagonists.

  • Experimental Phases:

    1. Low Dose (2 ug): Induced a transient fall in blood pressure due to Muscarinic stimulation (vasodilation and bradycardia).

    2. High Dose (50 ug): Induced a more profound fall in BP, but when repeated after Atropine (a muscarinic antagonist), it caused a sharp increase in BP and heart rate.

  • The "Nicotinic Action" of ACh: In the presence of Atropine, muscarinic receptors are blocked. The high dose of ACh then stimulates nicotinic receptors at the autonomic ganglia and the adrenal medulla, releasing adrenaline/noradrenaline and causing sympathetic-mediated vasoconstriction.

Muscarinic Receptor Subtypes and Signaling

  • M1 ("Neural"): Gq-coupled. Located in the CNS and gastric parietal cells. Increases IP3/DAG.

  • M2 ("Cardiac"): G_i-coupled. Located in the atria and AV node. Decreases cAMP and opens K^+ channels, leading to hyperpolarization and decreased heart rate (negative chronotropy).

  • M3 ("Glandular/Smooth Muscle"): G_q-coupled. Located in exocrine glands (sweat, salivary) and smooth muscle. Mediates contraction (e.g., bladder, gut) and stimulates Nitric Oxide (NO) release from vascular endothelium, leading to indirect vasodilation.

Nicotinic Receptor Pharmacology

  • Ganglionic Agonists: ACh, Nicotine (bicyclic), and DMPP. These stimulate both sympathetic and parasympathetic ganglia indiscriminately.

  • Ganglionic Antagonists (Blockers):

    • Hexamethonium: A classic competitive antagonist. It does not distinguish between sympathetic or parasympathetic ganglia.

    • Clinical Effect of Blockade: Depends on which system provides the "dominant tone" to an organ. For example, since the heart is under dominant parasympathetic tone, hexamethonium causes tachycardia. Since vessels are under sympathetic tone, it causes vasodilation (lowering BP).

Polybismethonium Compounds (Paton and Zaimis)

  • Structure-Activity Relationship: The distance between the two quaternary ammonium groups (n = number of carbon atoms) determines the site of action.

    • C_6 (Hexamethonium): Selective for ganglionic nicotinic receptors.

    • C_{10} (Decamethonium): Selective for the neuromuscular junction (skeletal muscle).

    • This research highlighted the structural differences between nicotinic receptor isoforms.