L10 - ACh Flashcards
describe synaptic synthesis, storage, release, reuptake, degradation of ACh
what is the common combination of subunits for the nAChR (for ACh) in the CNS
(2x a4) and (3xB2)
(and others)
or
5x a7
what is the common combination of subunits for the nAChR (for ACh) in muscle
2x a1, B1, 1x delta, 1x gamma
how many ACh binding sites are there on the nAChR and where
2
between a and B subunits
what are CNS (ACh) nAChRs permeable to
Na
K
Ca2+
what are muscle (ACh) nAChRs permeable to
mainly just Na and K
what types of a and B subunits of ACh nAChR are found in muscle?
a1
B1
what types of a and B subunit of ACh nAChRs are found in CNS
B2-4
a2-10 (excluding 8)
where is ACh found in the CNS
- cell bodies in caudate nuclei project into thalamus
- nuclei in septum project into cortex annd hippocampus
- cell bodies in magnocellular forbrain project into thalamus, olfactory system and cortex
- interneurones in striatum and retina
describe the differences between a (5x a7) and a (2x a4 + 3x B2) nAChR
(2x a4 + 3x B2) is equally permeable to Na and Ca
(5x a7) is 10 more permeable to Ca
5x a7 has faster desensitisation
it is also less sensitive to ACh (higher EC50)
what are the three important nuclei that are made up of ACh containing neurones
caudate nuclei
septum nuclei
magnocellular forebrain nuclei
ACh (across all types of receptors) can have 3 types of electrical responses, what are they?
- fast depolarisation fast inactivation (nAChRs)
- slow depolarisation slow inactivation (muscarinic via inhiibition of K channels)
- slow hyperpolarisation slow inactivation (muscarinic receptors via inhibition of Ca /Na channels or activation of K channels)
what type of receptors are muscarinic
GPCRs
how many subtypes of muscarinic recpeptor are there and where are they located
what muscarinic recepotrs are found postsynaptically
what G protein are they coupled to
M1, M3, M5
Gq/11
what is the effect of post synaptic, Gq/11 coupled M1, M3, M5 receptors
- activate PLC which breaks down PIP2 (reducing K channel opening)
- breakdown of PIP2 forms IP3 and DAG
IP3 acts on IP3 receptors on ER releasing Ca2+
DAG activated PKC which can go onto phosphorylate many proteins
what is the effect of pre synaptic, Gi/o coupled M2, M4 receptors
Gi activation reduces production of cAMP via inhibition of adenylate cyclase
By subunits of Go inhibit Ca2+ channel opening
what type of ACh related drug can treat motion sickness?
hyocine acts on chemoreceptor trigger zone to reudce motion sicnkess
what causes nocturnal frontal lobe epilepsy? (NFLE)
the autosomal dominant nAChR channelopathy
symptoms of nocturnal frontal lobe epilepsy
brief partial seizures during light sleep
describe the type of mutation that occurs in (NFLE)
point mutation S247F in the CHRNA4 gene ( gene for alpha4 subunit of nAChR)
describe the genetic linkage for nocturnal frontal lobe seizures
20q 13.2-13.3
same place as CHRNA4 gene (gene for alpha 4 subunit of nAChR)
what effect does the mutation in NFLE have on the receptor
the mutation occurs in TMD2 of the a4 subunit which affects the pore of the channel
it causes
- increased desensitisation of the channel (longer refractory period)
- sllow recovery from desensitisation
- so reduced Ca2+ permeability
how does the effects of the NFLE mutation lead to the symptoms observed?
reduced Ca2+ permeability of receptors on GABAergic neurones, means less NT (GABA) is released - so less inhibition in CNS
list some effects of Muscarinic ACh receptors in CNS
M1 -> involved in long term potentiation and memory
M2-> involved in analgesia and hypothermia
M5 -> knockout M5 reduced DA release
