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Cholinergic Mech.
Physiology and Pharmacology
| Question | Answer |
|---|---|
| Acetylcholine | A neurotransmitter used by Cholinergic nerves An ester of acetic acid and choline Chemical formula C7H16NO2+ |
| Where is ACh found | All autonomic ganglia Many autonomically innervated organs NMJ Also found in the CNS |
| Peripheral Nervous System | Divided into somatic and autonomic components |
| Somatic NS | Controls all voluntary muscular systems in the body Includes sensory and motor nerves Innervates limbs and body wall Controls skeletal muscle and external sensory organs |
| Autonomic NS | Independent of conscious control Conveys all output from CNS to body Regulates - heart muscle, endocrine/exocrine secretions, metabolism and smooth muscle contraction Split into sympathetic, parasympathetic and enteric |
| Parasympathetic NS | Preganglionic neurons have cell bodies in the brain stem and sacral spinal cord Axons of preganglionic neurons release ACh onto postganglionic neurons located near target organs |
| Sympathetic NS | Most preganglionic neurons originate in the spinal cord (thoracic level) Axons of these neurons release ACh onto postganglionic neurons within sympathetic ganglia. These then release norepinephrine onto target organs |
| Role of sympathetic and parasympathetic NS | Balance each other out Sympathetic - deals with stress and danger increasing energy and metabolism e.g. fight or flight Parasympathetic - counteracts this by lowering metabolic rate, slowing activity and restoring blood pressure/resting heart rate |
| Where is ACh released in the autonomic NS | All pre and post ganglionic parasympathetic neurons All pre-ganglionic sympathetic neurons From sympathetic postganglionic neurons on sweat glands |
| Biological mechanisms in ACh | Synthesis Storage/release Termination Receptor interaction |
| Synthesis of ACh | Two enzymes involved - Choline acetyltransferase and AChE Rate limiting step in ACh synthesis are Acetyl CoA from glucose metabolism and choline from high affinity uptake Nerves cannot make enough choline so it is taken up from the blood (from diet) |
| Storage of ACh | Stored in nerve endings in small, membrane limited vesicles Uptake of ACh into vesicles occurs through an energy-dependant pump that acidifies the vesicle The acidified vesicle then uses a vesicular ACh transported to exchange protons for ACh |
| Release of ACh | Arrival of AP at nerve terminal Entry of Ca via voltage gated channels Release of ACh from exocytotic vesicles docked in place Binding of ACh to receptors and inactivation |
| Termination of ACh | Main mechanism is hydrolysis by tissue acetylcholinesterase ACh binds briefly to receptors Following dissociation is is hydrolysed by AChE Linkage between choline and acetate is broken and acetate dissociates separately |
| Types of ACh receptor | Nicotinic - ligand gated ion channels impermeable to anions but permeable to cations Muscarinic - G protein coupled receptors Can be found on both sides of the synaptic cleft |
| Location of AChR | CNS - muscarinic and nicotinic Autonomic - Muscarinic and nicotinic Neuromuscular - nicotinic |
| Muscarinic receptors | Bind both ACh and muscarine Mainly at autonomic ganglia, organs innervated by parasympathetic NS, sweat glands and in the CNS G protein coupled receptor Single polypeptide - 7 transmembrane domains |
| Subclasses of mAChR | M1, M3 and M5 are excitatory receptors, cupled to Gq GPCRs to activate IP3 M2 and M4 are inhibitory and interact with Gi/Gq to inhibit adenylyl cyclase to reduce cAMP |
| Role of mAChR | Activation of M3 in smooth muscle produces response in organs e.g. bladder Activation of M2 lowers conduction velocity at SN and AV nodes M1, M4 and M5 are involved in complex CNS responses like memory, arousal, attention and analgesia |
| Nicotinic receptors | Binds both ACh and nicotine Located at NMJ, peripheral neurons (autonomic ganglia) and central neurons Ligand gated ion channels - undergo conformational change to allow Na entry |
| Subtypes of nAChR | N1 - located at neuromuscular junctions N2 - play a key role in transmission of cholinergic signals in ANS |
| Structure of NMJ nAChR | 5 polypeptides - two alpha, one beta, gamma and delta Binding surface is on alpha subunits Contain recognition sites for agonists, reversible antagonists and alpha toxins Ganglionic nAChR has only two subunits |
| Agonists of AChR | ACh binds to both muscarinic and nicotinic receptors Nicotine and Muscarine are more rigid molecules so bind specifically to one type |
| Antagonists | Atropine - only binds to muscarinic receptors Tubocurarine - only binds to nicotinic receptors |
| Physiology of nicotinic receptors | Activation causes opening of the channel Increases Na movement into cell leading to depolarisation and an AP Rapidly developing change is termed Fast Excitatory Postsynaptic Potential Gives a brief and fast response |
| Physiology of muscarinic receptors | Can be either excitatory or inhibitors Always slow on onset and long in duration as has to act via G proteins |
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