L10 Acetylcholine PDF

L10 Acetylcholine Be able to identify the major cholinergic nuclei in the brain Describe the heterogeneity of nicotinic receptors in the CNS Describe the heterogeneity of muscarinic receptors in the CNS Identify CNS diseases that involved the cholinergic system Describe an example of an acetylcholin...

L10 Acetylcholine Be able to identify the major cholinergic nuclei in the brain Describe the heterogeneity of nicotinic receptors in the CNS Describe the heterogeneity of muscarinic receptors in the CNS Identify CNS diseases that involved the cholinergic system Describe an example of an acetylcholine receptor channelopathy Summary of ACh synthesis, release and reuptake ACh neurochemistry Vesicular ACh transporter Choline Carrier AcCoA Choline Choline CAT CoA ACh ACh ACh Empty vesicle ACh Exocytosis ACh Acetate + choline AChE Acetylcholine synthesised from acetylCoA and choline catalysed by cholineacetyltransferase. It is taken up into vesicles by VAchT driven by a proton gradient. It is released from synaptic vesicles and diffuses to its receptors. It is recycled by acetylcholinesterase. Be able to identify the major cholinergic nuclei in the brain Ach is mainly used for long distance signalling but is also used at shorter neurons as well. Major cholinergic nuclei: GABA neurones in the striatum – roles in alzheimers and Parkinson’s disease. Hippocampus Cortex Septum – projects into hippocampus and cortex Thalamus Caudate nucleus – projects to thalamus Interneurons in retina/retinal ganglion cells ACh effects on CNS neurones The effect of ACh is decided by the receptor type. Nicotinic AChRs are ligand gated ion channels and muscarinic AChRs are g protein coupled receptors. Fast depolarisation: Mitigated by nicotinic AChRs. Slow depolarisation: Mitigated by muscarinic AChRs by switching off potassium channels. Slow hyperpolarisation: Mitigated by muscarinic AChRs by releasing intracellular calcium which activates calcium activated potassium channels and causes hyperpolarisation. Describe the heterogeneity of nicotinic receptors in the CNS Nicotinic ACh receptors are ligand gated cation channels (mainly Na+ and K+). Made of 5 subunits. In the CNS: 2 alpha and 3 beta and alpha only hmopentamers Most common in CNS: 2 alpha4 and 4 beta2 or 5 alpha 7. Different subunits have different properties e.g. different pharmacology, ionic permeability or denesitisation rates. Describe the heterogeneity of muscarinic receptors in the CNS Muscarinic AChRs are all GPCRs M1, M3 and M5 are found postsynaptically and are Gq coupled – excitatory – activate phospholipase C which activates IP3 and DAG which increases intracellular calcium concentration. M2 and M4 are coupled to Gi and Go so they are inhibitory and are dounf presynaptically. Drugs acting on acetylcholine receptors in the central nervous system Nicotinic drugs Agonists Epibatidine – novel analgesic Nicotine – dependency/recreational drug. Increases dopamine levels in mesocorticolimbic pathways. o Nicotine acts on presynaptic nAChRs to enhance DA release o But incidences of Alzheimer's, Parkinson's disease as well as IBS are significantly lower in smokers. o Smokers upregulate nAChRs Partial agonists: Varenicline – used for nicotine dependency – prevents withdrawal without providing the euphoric effect of nicotine so can wean someone off their dependency. Acetylcholinesterase inhibitors: Donepezil, galantamine, rivastigmine – improves duration of ACh in synaptic cleft – makes up for deficit in cholinergic neurons. Muscarinic drugs Antagonists: Mimic the effects of atropine benztropine biperiden orphenadrine procyclidine Above used as antiparkinson drugs Hyocine – used for motion sickness Identify CNS diseases that involved the cholinergic system Alzheimer’s–mAChRs–indirect therapeutic target Parkinson’s–mAChRs–therapeutic target Schizophrenia-mAChRs Pain – nAChRs - novel therapeutic target Neurodegeneration-nAChRs Drug dependency – nAChRs – therapeutic target Describe an example of an acetylcholine receptor channelopathy Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) – a nAChR channelopathy Point mutation in alpha 4 subunit S247F Effect of mutation: o Increased desensitisation – the channel switches off quickly. o No calcium release = inhibitory GABA vesicles in postsynaptic neuron not released = hyperexcitability = epilepsy.