Neurotransmission and Drug Action in Synapse

Pharmacological Agents and Drugs Acting on Synapses

• Drugs and pharmacological agents act on synapses in the nervous system, affecting neurotransmission
• The peripheral nervous system (PNS) is the focus of study, with its key neurotransmitters being acetylcholine (ACh) and noradrenaline (NA)

Neuromodulation of Synaptic Transmission

• The nervous system is divided into the central nervous system (CNS) and the PNS
• The PNS is further divided into the somatic nervous system and the autonomic nervous system
• The autonomic nervous system is then divided into the sympathetic and parasympathetic nervous systems
• Acetylcholine (ACh) is the main neurotransmitter in somatic nerves and pre-ganglionic fibres of the autonomic nervous system, along with post-ganglionic fibres in the parasympathetic nervous system
• Noradrenaline (NA) is the neurotransmitter in post-ganglionic fibres of the sympathetic nervous system

Acetylcholine (ACh)

• ACh is the key neurotransmitter in the peripheral nervous system, first identified by Dale in 1930
• ACh acts at neuromuscular junctions, all preganglionic fibres and postganglionic fibers of the parasympathetic nervous system
• ACh is synthesized in the presynaptic terminal from choline and acetyl-CoA
• ACh's action is terminated by its degradation by acetylcholinesterase
• 1921, Otto Loewi discovered the release of a chemical messenger (Vagusstoff) from the vagus nerve impacting heart rate

Pharmacology of the ACh Synapse

• 1921 Loewi's showed stimulation of vagus causes heart slowing via release of a substance he named Vagusstoff
• Acetylcholine (ACh) acts on two types of receptors: Nicotinic and Muscarinic
  • Nicotinic receptors are ionotropic receptors, ligand-gated ion channels found in autonomic ganglia and neuromuscular junctions.
  • Muscarinic receptors are metabotropic receptors, G-protein coupled receptors found in parasympathetic synapses with target organs like smooth muscle and cardiac muscle

Acetylcholine (ACh) Biosynthesis

• ACh is synthesized from choline and acetyl-CoA in the presynaptic terminal

Noradrenaline (NA)

• Noradrenaline (NA) is the main neurotransmitter at post-ganglionic sympathetic neurons.
• NA is a catecholamine synthesized from tyrosine, with its action terminated by reuptake into the presynaptic terminal
• NA receptors are of two major subtypes: alpha-adrenergic receptors and beta-adrenergic receptors. These receptors use cAMP as a second messenger.
• The drug amphetamine affects NA synapses by blocking reuptake

Noradrenergic Synapse

• Amphetamine blocks NA reuptake, increasing prolonged NA stimulation of postsynaptic neurons

Cholinergic Synapses

• Cholinergic synapses use ACh for transmission
• Two types:
  • Ionotropic receptor (nicotinic) - ligand-gated ion channels responsible for muscle contraction.
  • Metabotropic receptor (muscarinic) - G-protein coupled receptors affecting target organs like smooth muscle and cardiac muscle.

The Nicotinic Receptor

• The alpha subunit of the nicotinic ACh receptor has four transmembrane domains (M1, M2, M3, M4) with extramembrane sequences above and below

The Cholinergic Synapse ((i) e.g. NMJ and (ii) Atrial cells parasympathetic)

• The cholinergic synapse process of NMJ and atrial cells including ACh release, receptor binding, and subsequent depolarization/hyperpolarization and effects
• Different types of ACh receptors (ionotropic and metabotropic) have differing signalling pathways

G Protein-Coupled Receptor (GPCR) Signaling

• Ligand binding triggers G-protein activation
• Activated G-protein activates or inhibits downstream effectors(enzymes) like adenylate cyclase or phospholipase C, creating cascades of intracellular responses.

G-alpha Subunit of GPCRs

• G-alpha subunits (αs, Gi, Gq/11/12/13) are crucial for diversity in GPCR function, influencing different cellular processes.
• They differentially affect downstream targets, like ion channels or enzymes

GPCR Signaling Pathways

• GPCR signaling interacts with other signalling pathways, like those from hormones and growth factors.

Pharmacological Modulation of Cholinergic Synapses in the PNS

• Drugs affecting these synapses include agonists that mimic ACh effects and antagonists that block them.

Effects of Autonomic Stimulation

• Table providing sympathetic and parasympathetic effects on various organs (eye, heart, arterioles, lungs, gut, liver, and bladder)

Effect of β-blockers

• Graph showing the effect of the beta-blocker drug oxprenolol on heart rate.

Terminology

• Definitions for terms related to cholinergic neurotransmission, like cholinergic, cholinoceptor, muscarinic antagonist, mimetic (agonist), and lytic.

Pharmacology of the ACh Synapse: A Historical Prospective

• Details about historical discoveries of ACh synapse's function

Targets for drug action at the cholinergic synapse

• Detail about types of drugs that interact with different parts of the cholinergic synapse (pre-synaptic, synaptic, and post-synaptic inhibitors) and examples.

Muscarinic Receptor Subtypes

• Description of 5 different types of Muscarinic receptors (M1 to M5) with their main location, functions and activation pathways.

Diversity of Muscarinic Receptor function

• Description of different G proteins interacting with each subtype of muscarinic receptor

Drugs acting at Muscarinic Receptors

• Description of drugs stimulating muscarinic receptors (parasympathomimetics) and inhibiting muscarinic receptors (parasympatholytics)

Drugs acting at Muscarinic Receptors Tables

• Tables providing information about drug structures, receptor specificity, hydrolysis by AChE, and clinical uses

Effects of Muscarinic Agonists

• Details about effects of muscarinic agonists, including cardiovascular effects, smooth muscle effects, gland effects, and central effects.

Clinical Use of Muscarinic Agonists and Antagonists

• Main uses of muscarinic agonists (e.g., glaucoma treatment) and antagonists (e.g., topical treatment for pupil dilation)

Nice and easy way to remember!

• Diagram summarising different subtypes of muscarinic receptors, location of the subtypes, and related agonists and antagonists.

Overview of neurotransmitters in the PNS

• Diagram showing the pathways of different neurotransmitters (ACh, NA, adrenaline/epinephrine) in the peripheral nervous system.

Test your knowledge on the sympathetic and parasympathetic nervous systems, including the effects of neurotransmitters, GPCR signaling, and pharmacological agents like β-blockers. This quiz covers various aspects of neurotransmission, including receptor types and the impact of drugs on cardiovascular function.