Neurotransmission & Drug Action in Synapses PDF

Pharmacological agents and Drugs acting on synapses Dr. Mohammad K. Hajihosseini BIO5004A [email protected] September 2024  Neuromodulation of synaptic transmission Nervous System CNS PNS Brain...

Pharmacological agents and Drugs acting on synapses Dr. Mohammad K. Hajihosseini BIO5004A [email protected] September 2024  Neuromodulation of synaptic transmission Nervous System CNS PNS Brain Spinal cord Sensory Somatic System Autonomic Nervous Nervous System System Focus: PNS and its main neurotransmitters: Acetylcholine Sympathetic Enteric Parasympathetic Noradrenaline Nervous Nervous Nervous System System System 1  Acetylcholine ACh is the major neurotransmitter of the PNS , first identified by Dale in 1930 It is the neurotransmitter of the somatic efferent system (neuromuscular junction), all pre-ganglionic fibres of the autonomic nervous system and the post-ganglionic fibres of the parasympathetic nervous system 2  Pharmacology of the ACh synapse: A historical prospective 1921 Leowi showed that stimulation of the vagus nerve causes the heart to slow via release of a substance he named Vagusstoff 3 Acetylcholine (Ach) biosynthesis ACh is synthesized from choline and acetyl CoA in the pre-synaptic terminal 4  Noradrenaline (norepinephrine) Noradrenaline (NA) is the neurotransmitter at post-ganglionic sympathetic neurons NA is a catecholamine synthesized from Tyrosine The action of NA is terminated by reuptake into the presynaptic terminal NA receptors have 2 major sub-types: – α-adrenergic receptors (G protein coupled receptors – linked to Ca2+ release (α1) or inhibition of adenylate cyclase (α2)) – β-adrenergic receptors (GPRCs linked to stimulation of adenylate cyclase (cAMP↑)) 5 Noradrenergic synapse The drug Amphetamine works in part by blocking or competing with NA for its uptake/ removal from the synaptic cleft Effect: more prolonged NA stimulation of post- synaptic neurons 6  Acetylcholine (Ach) - Cell Signalling ACh acts on two types of receptors: - Nicotinic receptors (ionotropic receptors) Ligand-gated ion channels Found for example in autonomic ganglia and at the neuromuscular junction – Muscarinic receptors (metabotropic receptors) G-protein coupled receptors Found for example at parasympathetic synapses with target organ eg. Smooth muscle, cardiac muscle 7  Cholinergic Synapses → muscle contraction Eg → decreased heart rate Source: Boron & Boulpaep. Medical Physiology. Saunders 8 The Nicotinic Receptor Source: Boron & Boulpaep. Medical Physiology. Saunders 9 The Cholinergic Synapse (i) e.g. NMJ (ii) Atrial cells (parasympathetic) 10 Source: Boron & Boulpaep. Medical Physiology. Saunders G Protein-Coupled Receptor (GPCR) Signaling 11  G-alpha subunit of GPCR occurs in diverse forms and provides for diversity of function G alpha (a) Subtypes: Gi Gs Gq G12,13 12 GPCR signaling integrates the cells’ response to other signaling pathways 13 Pharmacological modulation of Cholinergic synapses in the PNS 14  Effects of Autonomic stimulation Target Organ Sympathetic Parasympathetic Eye Dilates pupil Constricts pupil Contracts ciliary muscle Heart Increases rate and force of Decreases rate and force contraction (noradrenergic of contraction effect) Arterioles Constricts (↓flow to organs; ↑bp) Exceptions: dilation in skeletal muscle and coronary circulation Lungs Relaxation of bronchial smooth Contraction of bronchial muscle smooth muscle Gut ↓motility ↑motility Contraction of sphincters Relaxation of sphincters Liver Glycogenolysis Gluconeogenesis Bladder Relaxation Contraction 15 Effect of ‘β-blockers’ (β-adrenergic receptors) on Heart Rate Source: Rang, Dale & Ritter. Pharmacology. Churchill Livingstone 16  Terminology ‘Cholinergic’ – neurons secreting ACh ‘Cholinoceptor’ – receptor for ACh Muscarinic antagonist = muscarinic blocker = an anti-muscarinic drug - ‘Mimetic (agonist)’ – mimicking or promoting the action of…. eg. sympathomimetic - ‘lytic’ – inhibiting or terminating the action of…. e.g. sympatholytic 17  Pharmacology of the ACh synapse: A historical prospective 1869 The actions of muscarine and atropine on the heart were shown: – Muscarine (an alkaloid from the fungus Amanita muscaria) could slow heart rate – Atropine (an alkaloid from Atropa belladonna – deadly nightshade) could block the actions of muscarine and vagal nerve stimulation 18  Pharmacology of the ACh synapse: A historical prospective 1905 The actions of nicotine and curare at the neuromuscular junction were reported (Langley) – Nicotine (an alkaloid from the tobacco plant Nicotiana tabacum) could stimulate contraction of skeletal muscles – Curare (an extract from South American plants including Chondrodendron tomentosum) could block the actions of nicotine at the NMJ (poisoned arrows of SA Indians) 19  Targets for drug action at the cholinergic synapse (I) pre-synaptic inhibitors Other examples: 1. Bacterial infection (ClostridiumTetani) Tetanus toxin (TT) prevents fusion of vesicles with pre- synaptic membrane TT works on inhibitory neurons - therefore causes an increase in muscle contraction 20  Targets for drug action at the cholinergic synapse (ii) synaptic and post-synaptic inhibitors -Other examples: 1. Nerve gas - ‘Sarin’ -Diffusion through blood stream - Inhibits acetylcholinesterase, resulting in uncontrolled muscle contraction 2. Tetrodotoxin Produced in ovaries of Puffer fish - Binds to voltage-gated sodium channels and prevents action potential formation (Ingestion can be fatal) Novichok Promotes degradation 21 of acetylcholinesterase  Targets for drug action at the cholinergic synapse (ii) synaptic and post-synaptic inhibitors -Other examples: 1. Nerve gas - ‘Sarin’ -Diffusion through blood stream - Inhibits acetylcholinesterase, resulting in uncontrolled muscle contraction 2. Tetrodotoxin Produced in ovaries of Puffer fish - Binds to voltage-gated sodium channels and prevents action potential formation (Ingestion can be fatal) 21a  Reminder: there are two types of Cholinergic synapses - Nicotinic receptors (ionotropic receptors) Ligand-gated ion channels Found for example in autonomic ganglia and at the neuromuscular junction – Muscarinic receptors (metabotropic receptors) G-protein coupled receptors (GPCR)s Found for example at parasympathetic synapses with target organ eg. Smooth muscle, cardiac muscle 22  Location of Muscarinic receptor action Muscarinic receptors are classic G-protein coupled receptors In the PNS, they are found at the synapse of post-ganglionic parasympathetic nerve terminals Exception to the rule! 23  Muscarinic Receptor subtypes There are 5 muscarinic receptor subtypes – M1 to M5 – M1 – “Neural” (I.e expressed by cells of neural origin) mainly in CNS, some glands eg. Gastric Signal via IP3/Ca2+ pathway and inhibition of K+ channels (slow EPSP) – M2 – “Cardiac” Mainly heart, plus CNS Signal via cAMP (↓) and activation of K+ channels Effect: slows the speed of depolarization – M3 – “Glandular/smooth muscle” Mainly glands (promotes secretion) and smooth muscle (e.g. vasoconstriction of lung, but vasodilation of blood vessels) Signal via IP3/ Ca2+ – M4 and M5 Mainly in CNS, functional role not well defined 24  Diversity of Muscarinic Receptor function is via their interaction/s with specific subtypes of GPCRs – M1 Gi, GS, Gq – M2 Gi – M3 Gq – M4 Gi – M5 Gq 25  Drugs acting at Muscarinic Receptors Drugs stimulating muscarinic receptors are termed parasympathomimetics as their effects resemble stimulation of the parasympathetic system Drugs inhibiting muscarinic receptors are termed parasympatholytics due to their inhibitory effects at the parasympathetic nervous system The effects of the parasympathetic nervous system are mediated by ACh acting at muscarinic receptors at the target organ 26 Drugs acting at Muscarinic Receptors 27  Drugs acting at Muscarinic Receptors (M3) NB. Most agonists at muscarinic receptors are non-selective and may simultaneously activate multiple muscarinic receptor types 28  Effects of Muscarinic Agonists Cardiovascular – Bradycardia (heart beat