Cholinergic Neurotransmission

• "Acetylcholine (ACh)"

  Attribution: The Noted Anatomist  Acetylcholine (ACh) https://www.youtube.com/watch?v=MJECqcYJhmo The Noted Anatomist Youtube Channel https://www.youtube.com/channel/UCe9lb3da4XAnN7v3ciTyquQ

• Transmitter Synthesis and Degradation

  • Acetylcholine is synthesized from the immediate precursors acetyl coenzyme A and choline in a reaction catalyzed by choline acetyltransferase (choline acetylase).

• Acetylcholinesterase

  • Rapid inactivation of acetylcholine is mediated by acetylcholinesterase.

  • Acetylcholinesterase is present at ganglia, visceral neuroeffector junctions, and neuromuscular junctional endplates.

  • Another type of cholinesterase, called pseudo-cholinesterase or butyrylcholinesterase has limited presence in neurons, but is present in glia. Most pseudocholinesterase activity is found in plasma and liver.

  • Pharmacological effects of anti-cholinesterase drugs are due to inhibition of acetylcholinesterase.

• Acetylcholine Storage and Release

  • Small random release of acetylcholine-quanta, producing miniature end-plate potentials (mepps) , are released by presynaptic terminals.

    • These small currents were linked to ACh release since anticholinesterases (neostigmine) increased their effects, while cholinergic receptor antagonist (tubocurarine, a nicotinic receptor blocker) blocked.

  • Anatomical counterpart to the electrophysiological quanta is the synaptic vesicle.

  • The model is based on the nicotinic, skeletal neuromusclar junction.

  • Synchronous exocytotic release of many more quanta, dependent on Ca²⁺ occur when an action potential reaches the terminal.

  • Exocytotic release of acetylcholine and other neurotransmitters is inhibited by toxins elaborated by Clostridium botulinum.

• Botulism

  • Botulism is caused by the most potent neurotoxins known. The neurotoxins are produced and liberated by Clostridium botulinum.

  • C. botulinum, ubiquitously found in soil and marine environments, is a group of gram positive anerobes that form spores.

     

  • Eight distinct toxins have been characterized, all but one being neurotoxic.

  • Botulinum neurotoxin affects cholinergic nerve terminals:

    • Postganglionic parasympathetic endings

    • Neuromuscular junctions

    • Peripheral ganglia

    • CNS is not involved.

  • Botulinum neurotoxin prevents acetylcholine release:

    1. Binds presynaptically

    2. Internalized in vesicular form

    3. Released into the cytoplasm

    4. The toxin(s), (zinc endopeptidases) causes proteolysis of components of the neuroexocytosis system.

• Cholinergic Transmission: Site Differences

  • Skeletal Muscle

    • Neurotransmitter: Acetylcholine

    • Receptor Type: Nicotinic

    • Sectioning and degeneration of motor and post-ganglionic nerve fibers results in:

      • Enhanced post-synaptic responsiveness, denervation hypersensitivity.

        • Denervation hypersensivity in skeletal muscle is due to

          1. Increased expression of nicotinic cholinergic receptors

          2. Spread to regions away from the endplate.

Autonomic Effectors

• Neurotransmitter: Acetylcholine

• Receptor type: Muscarinic

• Effector coupled to receptor by a G protein

• In smooth muscle and in the cardiac conduction system, intrinsic electrical activity and mechanism activity is present, modifiable by autonomic tone.

  • Activities include propagated slow waves of depolarization: Examples: intestinal motility and spontaneous depolarizations of cardiac SA nodal pacemakers.

• Acetylcholine decreases heart rate by decreases SA nodal pacemaker phase 4 depolarization.

  • The cardiac action potential associated with HIS-purkinje fibers or ventricular muscle consists of five phases

    • Phase 0 corresponds to Na⁺ channel activation.

      • The maximum upstroke slope of phase 0 is proportional to the sodium current.

      • Phase 0 slope is related to the conduction velocity in that the more rapid the rate of depolarization the greater the rate of impulse propagation.

    •  Phase 1 corresponds to an early repolarizing K⁺ current. This current like the Phase 0 sodium current is rapidly inactivated.

    •  Phase 2 is the combination of an inward, depolarizing Ca²⁺ current balanced by an outward, repolarizing K⁺ current (delayed rectifier).

    • Phase 3 is also the combination of Ca²⁺ and K⁺ currents

      • Phase 3 is repolarizing because the outward (repolarizing) K⁺ current increases while the inward (depolarizing) Ca²⁺ current is decreasing.

    • Phase 4 in normal His-Purkinje and ventricular muscle cells is characterized by a balance between outward Na+ current and inward K+ current. As a result, the membrane potential would normally be flat.

      •  In disease states or for other cell types (SA nodal cells) the membrane potential drifts towards threshold.

        • This phenomenon of spontaneous depolarization is termed automaticity and has an important role in arrthymogenesis.

      • Rate of phase 4 depolarization is decreased by an increase in K⁺ conductance, which leads to membrane hyperpolarization (takes longer to reach threshold).

Autonomic Ganglia

• Neurotransmitter: Acetylcholine

• Receptor type: Nicotinic

• Generally similar to skeletal muscle site: initial depolarization is due to receptor activation.

  • The receptor is a ligand-gated channel.

Blood vessels

• Choline ester administration results in blood vessel dilatation as a result of effects on prejunctional inhibitory synapses of sympathetic fibers and inhibitory cholinergic (non-innervated receptors).

  • In isolated blood vessel preparations, acetycholine's vasodilator effects are mediated by activation of muscarinic receptors which cause release of nitric oxide, which produces relaxation.

Signal Transduction

• Nicotinic Receptors

  • Ligand-gated ion channels

  • Agonist effects blocked by tubocurarine

  • Receptor activation results in:

    • Rapid increases of Na⁺ and Ca²⁺ conductance.

    • Depolarization

    • Excitation

  • Subtypes based on different subunit composition:  muscle and neuronal classification.

• Muscarinic Receptors

  • G-protein coupled receptor system

  • Slower responses

  • Agonist effects blocked by atropine

  • At least five receptor subtypes have been described by molecular cloning. 

    • Variants have distinct anatomical locations and differing molecular specificities.

   

  Leflowitz, RJ, Hoffman BB and  Taylor P:  Neurotransmission and Somatic Motor Nervous Systems, In Goodman and Gilman's The Pharmacological Basis of Therapeutrics (Hardman JG Limbird LE Molinoff PB Ruddon RW and Gilman A.G., eds)  The McGraw-Hill Companies Inc., 1996, pp 112-137.