Acetylcholine Receptors Flashcards
Explain ACh production and degradation.
Acetyl coA + choline —-cholineacetyltransferase—> acetylcholine + coA.
ACh –AChE–>acetate and choline…choline is recycled.
Explain some ACh pathways.
Caudate –> thalamus
magnocellular forebrain bundle –> thalamus and cortex
Septum –> hippocampus
GABA neurones in striatum –>RGC.
Dose Ach have the same effect on all neurones?
NO!
1) Fast depolarisation - nicotinic
2) Slow depolarisation - muscarinic
3) Slow hyperpolarisation - muscarinic.
Explain the NICOTINIC ACh receptors.
Ligand gated cat ion channels (Na+ in, K+ out, Ca+ in) 5 sunbunits CNS: 2 alpha, 3 beta or 5 alpha. alpha 2-10 (not 8) beta 2-4
Explain the alpha4(2) beta 2(3) receptor.
Ach Ec50 = 15micromolar Alphabungarotoxin insenstive Fast desensitisation pCa/pNa = 1 Thalamus and cortex.
Explain the alpha 7(5) receptor.
Ach Ec50 = 90 micromolars. Alphabungarotoxin sensitive. Very fast depolarisation. pCa/pNa = 10 Hippocampus and cortex.
Different (combinations of subtype) receptors have…
Different pharmacology, different ionic permeabilities, different desensitisation rates, different locations in the CNS.
Name a nicotinic agonist.
Epibatidine - novel analgesic in clinical trials.
Nicotine
Explain how smoking provides positive feedback.
Increase dopamin int eh mesocorticolimbic system, act on presynaptic nAChR to enhance DA release, smoker upregulate nAChR, DA enhancement = positive feedback.
Give a partial nictotinc agonist.
Varenicline - used for nicotinic dependency.
Name an acetylcholinesterase inhibitor.
Rivastigmine - used for dementia in AD.
Explain a channelopathy of nACHR
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)
Breif, partial seizures during light sleep - often perceived as nightmares.
20q13.2-13.3
Gene - CHRNA4 - alpha 4 subunit of nAChR.
Point mutation - S247F.
NO CA++ PERMEABILITY.
Increase desentisation - no Ca++ in, no GABA release
Where are M1 receptors found - what Gprotein are the linked to?
Cortex, hippocampus and striatum. Gq linked (incrase PLC, IP3, DAG etc)
Where are M2 receptors found - what Gprotein are the linked to?
Basal forebrain, thalamus, pons, cerebellum, hypothalamus.
Gi/o - decrease cAMP…inhibit Ca++ channels.
Where are M3 receptors found - what Gprotein are the linked to?
Low levels all over the CNS - Gq
Where are M4 receptors found - what Gprotein are the linked to?
Striatum
Gi/o
Where are M5 receptors found - what Gprotein are the linked to?
Substania nigra - Gq.
Name 2 Muscarinic antagonists.
Procyclidine - Anti PD
Hyocine - motion sickness.
Nicotinic - alpha 3 knockout.
LETHAL.
Nicotinic - alpha 4 KO
Decrease nicotinic analegsia.
Nicotinic - Alpha 7 KO?
No major changes.
Nicotinic - Beta 2 KO?
Altered learning, loss of nicotine dependance.
Nicotinic - B3 KO?
increase locomotor activity and decrease startle response.
Muscarninc - M1 KO?
Decrease LTP, learning and memory
