Cholinergic Signalling Flashcards
Which diseases are caused by disfunction of cholinergic signalling?
AD, myasthenia gravis
Which was the first NT to be identified and when?
Ach - 1915
How does acetylcholine act in the neuron?
As a neurotransmitter and a neuromodulator at the synapse
Which enzyme synthesises Ach?
ChAT ( choline acetyl transferase)
Which enzyme degrades Ach?
Acetylcholinesterase
How does Ach affect the somatic system?
At muscle causes contraction
How does Ach affect the sympathetic NS?
released from preganglionic synapses or from nerve to adrenal medulla, causing the release of epinephrine/norepinephrine
How does Ach affect the parasympathetic NS?
Ach as a NT in pre and post ganglionic neurons - feed breed, rest and digest
How is it that Ach can have such different effects in the para and sym. NS?
Different receptors
Where are ionotropic Ach receptors involved?
preganglionic synapse and skeletal muscle
Where are metabotropic Ach recpetors?
Post ganglionic in parasympathetic NS
What is an agonist which mimics Ach for ionotropic receptors?
nicotine
Which ions have ionotropic Ach receptors?
Na+ , K+, Ca2+
What are the characteristic of ionotropic Ach receptors?
- Short duration – millisecond response
- 5 SU
- 5 types of subunit combinations: alpha (1-10), beta (2-5), delta, epsilon and gamma
What allows Ach agonist/antagonist drugs to be specific to certain areas of the nervous system
Different receptor type
What is an agonist for metabotropic Ach receptors?
Muscarine
What is an inverse agonist for metabotropic Ach receptors?
Atropine
What are the characteristics of the metabotropic Ach receptors?
- GPCRs
- 7 TM domains
- Long duration – act through second messengers (seconds)
- Excitatory or inhibitory
- Can indirectly activate ion channels
Describe the different types of muscarinic Ach receptors
- M1 to M5 types – all in CNS
- M1 – secretory
- M2 - cardiac
- M3 - smooth muscle
What is the effect of Ach at the NMJ?
Release of Ach at NMJ when activated – causes Na+ influx through Ach receptors to initiate a muscle AP, this causes Ca2+ release and then muscle contraction
What is the main symptom of mysasthenia gravis?
increased muscle weakness on activity?
What is the cause of myasthenia gravis?
Auto antibodies against nAchR, muscle-specific kinase (Musk), lipoprotein-related protein 4 (LRP4) and agrin
Describe Ach breakdown
- By acetylcholine esterase enzyme
- Really rapid – highest catalytic rate enzyme known
- Four subunit composition coupled by a sulphydryl linkage to collagen or Proline Rich Membrane anchor to form symmetric form (PRiMA).
- Anchored to ECM of synapse so can’t diffuse away
What are the similarities between organophosphates and AD?
- Block of activity of acetylcholine esterase
- Accumulation of Ach in synapse leading to chronic depolarisation
- Antidote: Pralidoxime – binding couples nerve agent and displaces nerve agent from the binding site
- Ageing – permanent binding
- Symptoms: SLUDGEM- salivation, lacrimation, urination, defecation, GI upset, emesis and miosis
What is the treatment for organophosphates ?
• Treatment:
o Atropine- CNS penetrant, acute relief from parasympathetic activation, acts on muscarinic receptors in the CNS
o Diazepam – Reduces release of Ach from the synapse, anticonvulsant drug, CNS effect
o Pralidoxime – Reactivating agent, peripheral paralysis reversal by re-activating AchE, thus allowing metabolism of Ach. CNS non-penetrant
What are hte uses of AchE for disease?
- Myasthenia gravis – Use to prolong Ach in NMJ to improve neuromuscular transmission
- Alzheimers – AchE inhibitors potentiate Ach synapse levels and thus potentiate cholinergic action e.g. Donepezil, rivastigmine and galantamine are reversible selective inhibitors of AchE, show temporary benefit 12-24 months, do not alter the course of the disease
