L10: ACh Flashcards
What are the characteristics of the nicotinic acetylcholine receptor (nAChR) in the PNS?
- nAChR in the PNS has 5 subunits with 4 domains each.
- permeable to Na+, K+ & Ca2+ ions
- In muscles, composition typically = 2α1, β1, δ/γ/ε (embryo) subunits.
- in CNS composition includes = 2α, 3β, or 5α subunits forming homopentamers
- humans have 7 alpha subtypes of nAChRs
What are the common subunit combinations of nAChRs in the CNS and where are they found?
- Common combinations in the CNS include 2α4, 3β2, or 5α7 subunits.
- 2α4, 3β2 nAChRs - found in thalamus & cortex, exhibit fast activation, and not sensitive to alpha-bungarotoxin.
- 5α7 nAChRs - found in the hippocampus & cortex, have lower sensitivity to Ach & show very fast desensitization
Where is the binding site for acetylcholine (Ach) on the nAChR?
The binding site for acetylcholine (Ach) occurs at the alpha-beta interphase
How do 2α4, 3β2, and 5α7 nAChRs differ in their characteristics and response to alpha-bungarotoxin?
2α4, 3β2 nAChRs:
- not sensitive to alpha-bungarotoxin
- show fast desensitization
- have 1 Ca2+ for every 1 Na+ during activation
5α7 nAChRs:
- sensitive to alpha-bungarotoxin
- exhibit very fast desensitization
- 10 Ca2+ ions for every 1 Na+ ion during activation.
What are the subunit compositions of nAChRs in muscles and the CNS?
muscles = typically 2α1, β1, δ/γ/ε (embryo) subunits.
CNS = includes 2α, 3β, or 5α subunits forming homopentamers.
How is acetylcholine (ACh) synthesized and broken down in the nervous system?
- ACh is synthesized by the enzyme choline acetyltransferase (ChAT).
- Choline, obtained from the diet, serves as a precursor for ACh synthesis.
- After release, ACh is broken down by acetylcholinesterase (AChE)
Where are the nuclei in the CNS that produce and release acetylcholine (ACh)?
- caudate (cell bodies) projecting to thalamus
- septum projecting to the cortex & hippocampus
- magnocellular forebrain nuclei projecting to thalamus, cortex, or olfactory regions
What are some examples of neurons that transmit acetylcholine (ACh) in the CNS?
- short interneurons in CNS, e.g. such as in striatum - interact with dopaminergic and GABAergic systems.
- there are also small interneurons in the retina that transmit ACh
How does acetylcholine (ACh) affect CNS neurons?
- ACh can cause fast depolarization (possibly mediated by nicotinic receptors)
- can also lead to slow depolarization through G protein-coupled receptors (GPCRs).
- some muscarinic receptors can produce a slow hyperpolarization of neurons
What are the subtypes of muscarinic receptors in the CNS and where are they located?
M1 receptor: Found in the cortex, hippocampus, and striatum (post-synaptic).
M2 receptor: Present in the basal forebrain, thalamus, pons, cerebellum, and hypothalamus (pre-synaptic).
M3 receptor: Occurs at low levels throughout the CNS (post-synaptic).
M4 receptor: Located in the striatum (pre-synaptic).
M5 receptor: Found in the substantia nigra (post-synaptic)
What are the main functions and G protein coupling of muscarinic receptor subtypes in the CNS?
M1 receptor: Gq/11 protein-coupled, activates PLC (phospholipase C).
M2 receptor: Gi/o protein-coupled, pre-synaptic.
M3 receptor: Gq/11 protein-coupled, activates PLC.
M4 receptor: Gi/o protein-coupled, pre-synaptic, with inhibition of AC (adenylyl cyclase) enzyme by alpha i and calcium channel inhibition by Go betagamma subunit.
M5 receptor: Gq/11 protein-coupled, activates PLC
What are the effects of ACh on CNS neurons and the different types of neurons that transmit ACh?
- Effects on CNS neurons: Fast depolarization through nicotinic receptors & slow depolarization via GPCRs (G protein-coupled receptors).
- Neurons that transmit ACh: Caudate, septum, magnocellular forebrain nuclei, short interneurons in the striatum and retina
Name some nicotinic agonists and their uses
Epibatidine
Nicotine
Name a partial agonist of nicotinic receptors and its specific target
Varenicline
Specific Target: α4 nicotinic receptors
Name some acetylcholinesterase inhibitors and their uses
Donepezil
Galantamine
Rivastigmine
What are the main therapeutic uses of acetylcholinesterase inhibitors?
Alzheimer’s Disease
Dementia
How does nicotine affect dopamine levels in the brain?
↑ dopamine levels in mesolimbic pathway
- Acts presynaptically on nicotinic acetylcholine receptors (nAChRs) to enhance dopamine release
- Upregulates nicotinic receptors in the brain
Name some muscarinic antagonists and their use
Benztropine
Biperiden
Procyclidine
Use: Early stages of Parkinson’s disease
What is the use of hyoscine?
Motion sickness
What is Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) and how is it related to nAChRs
- a type of epilepsy that has an autosomal dominant inheritance pattern
- associated with mutations in nicotinic acetylcholine receptors (nAChRs).
- symptoms: brief partial seizures during light sleep, which are often perceived as nightmares
What is the genetic linkage and gene location associated with the mutation in nAChR?
Genetic Linkage: 20q13.2-13.3
Gene codes for: alpha4 subunit of the nicotinic acetylcholine receptor (nAChR)
What is the specific point mutation associated with the nAChR?
Point Mutation: S247F
The mutation is located at the pore region of the nAChR.
What are the effects of the S247F mutation on the nAChR?
- mutated channel lacks Ca2+ permeability
- still allows some Na+ entry but no Ca2+ entry, leading to reduced GABA release.
- mutated channel exhibits increased desensitization.
- shows slow recovery from desensitization.
- mutated channel has no Ca2+ permeability.
