2.6 Cholinergic Physiology Flashcards
Where in the somatic and autonomic nervous systems is acetylcholine (ACH) used as a neurotransmitter
ACH is the main neurotransmitter in the somatic nervous system. In the autonomic nervous system, the sympathetic nervous system uses ACH as the preganglionic neurotransmitter and the parasympathetic nervous system uses ACH as the preganglionic and postganglionic neurotransmitter.
Discuss the cholinergic system in the central nervous system
Cholinergic transmission is found in the forebrain, midbrain and brain stem. The receptors can be pre or post synaptic and can be involved in arousal, reward, learning, memory and motor control. Ccholinergic synaptic transmission problems are associated with diseases such as alzheimers and parkinsons
Describe the synthesis and release of acetylcholine as a neurotransmitter across the synaptic cleft.
Choline is cotransported into the cell along with sodium by specific protein transporters. ACH is made by acetyl coenzyme A linking to choline, combining by the enzyme choline acetyltransferase. There are specific cotransporter proteins that move hydrogen ions out of vesicles and ACH into vesicles to build up a high concentration of ACH in the vesicles. As voltage travels along the presynaptic membrane, voltage gated calcium channels open to allow calcium into the cell. Calcium ions bind to SNARE proteins on the vesicles, this promotes the vesicles to fuse with the membrane and release the ACH into the synaptic cleft via exocytosis. Once the ACH has bound to the receptors on the postsynaptic membrane, acetylcholineesterase in the post synaptic membrane then breaks down ACH back into choline and acetate, which then travels back across the synaptic cleft to the presynaptic membrane.
What are the 2 types of cholinergic receptor
nicotinic receptors and muscarinic receptors
What type of receptor are nicotinic receptors
Ionotropic receptors that are ligand gated cation sensitive channels
What type of receptor are muscarinic receptors
Metabotropic receptors that are G protein coupled with either cAMP or Ca2+ as the secondary messengers
Where are nicotinic receptors found
In the CNS, autonomic ganglia and neuromuscular junctions
Describe the 2 types of nicotinic receptor
There are Nn receptors and Nm receptors. Nn receptors are found in the CNS and autonomic ganglia but Nm receptors are found at neuromuscular junctions. Nicotinic receptors are made of 5 protein subunits, Nm and Nn are composed of different subunits.
How many ACH molecules are required to open a nicotinic receptor channel
2
How do nicotinic receptors allow for a fast EPSP
The kinetics of ACH binding and dissociation are very fast, also the action of acetylcholinesterase makes the effects of ACH at the receptor very fast.
What can happen to nicotinic receptors following prolonged activation of ACH
They can become desensitised to high levels of ACH
Are nicotinic receptors more predominant in the sympathetic or parasympathetic nervous system
Sympathetic nervous system
Describe how nicotinic receptors are selective for Na+ and K+
More Na+ enters than K+ that leaves, this causes depolarisation.
Describe the structure of muscarinic receptors
A transmembrane protein that wraps around the membrane 7 times and is attached to a G protein
What are the 2 options for G proteins attached to the muscarinic receptor
They are either excitatory or inhibitory
What are the 5 types of muscarinic receptor and are they excitatory or inhibitory
M1 - excitatory
M2 - inhibitory
M3 - excitatory
M4 - inhibitory
M5 - excitatory
Which area are each of the muscarinic receptors involved in
M1 - CNS, autonomic ganglia, glands and parietal cells
M2 - cardiac muscle, autonomic ganglia and CNS
M3 - Smooth muscle and exocrine glands
M4 - CNS
M5 - CNS
Give some key excitatory and inhibitory responses following muscarinic activation
Key excitatory effects include increasing Ca2+ concentration and increasing MAP kinases
Key inhibitory effects include decreasing adenyl cyclase and decreasing voltage operated Ca2+ channels
Are muscarinic receptors more predominant in the sympathetic or parasympathetic nervous system
Parasympathetic nervous system
What are the areas in cholinergic transmission that can be targeted with drugs
-targeting the ACH receptors with agonists and antagonists
-to block calcium channels
-to block acetylcholinesterase
-to block the choline cotransporter
Describe acetylcholinesterase (AChE) inhibitors (aka anticholinesterases)
By blocking the action of acetylcholinesterases, they elevate the synaptic concentration of ACH therefore enhancing the postsynaptic effects of ACH. They are known as parasympathomimetics as they have the same effect as the parasympathetic nervous system.
Examples include;
- simple alcohols e.g edrophonium (have a short duration of action, useful for diagnosing myasthenia gravis and eaton lambert)
-carbamic acid derivatives e.g neostigimine and physostigmine, they are hydrolysed by AChE to increase the half life of AChE inhibition, has a longer duration of action (useful for treating MG)
-organophosphates e.g parathion and sarin, irreversible, toxic, used in pesticideds
What are the negative effects of AChE inhibitors
-excessive muscarinic stimulation (salivation, lacrimation, miosis, diarrhea, bradycardia)
-excessive nicotinic stimulation (muscle weakness and paralysis)
-chemical warfare (can be used as a nerve gas causing muscle weakness or paralysis)
Give some muscarinic receptor agonists
- carbachol targeting circular muscle in the eye causing it to contract which alleviates glaucoma
- bethanocol targeting smooth muscle in GI tract, bladder and urinary tract to restore GI tract and U tract motility after surgery
- pilocarpine tagreting salivary glands causing increased salivation which benefits xerostomia
Why are muscarinic receptor antagonists known as parasympatholytics
Because they prevent the parasympathetic response and allow the sympathetic response to dominate
Give some examples of competitive muscarinic receptor antagonists
The prototype is atropine which is a plant alkaloid, other egs include;
- scopolamine used to treat nausea, motion sickness and intestinal cramp
- pirenzepine to treat peptic ulcers
- ipratropium reduces bronchial secretions to treat chronic obstructive pulmonary disease
What are competitive nicotinic antagonists used for
They act on Nm nicotinic receptors on neuromuscular junctions to prevent depolarisation and skeletal muscle contraction, causing flaccid paralysis. However the effects of this paralysis can be overcame by increasing Ach levels, e.g through a AChE. They are more selective for Nm receptors than Nn. Drugs include D-tubocurarine (plant alkaloid), pancuronium (long acting), vecuronium (intermediate acting), mivacurium (short acting) however side effects include hypertension, apnea, bronchospasm, salivation, flushing and respiratory failure.
Dsecribe nicotinic agonists
In high levels, they can cause short term paralysis and depolarisation by making the receptors desensitised via prolonged activation. e.g succinylcholine
What is a drug that prevents choline re-uptake with Na cotransporter in presynaptic neuron
Hemicholinium
What is a drug that prevents vesicular storage of ACH
Vesamicol
What is a drug that degrades SNARE proteins and prevents vesicle fusion and exocytosis
Botulinum Toxin (BOTOX)
