Acetylcholine and others Flashcards
1
Q
what are the 3 main cell groups in the periphery that ACh is found
A
- Pedunculopontine / laterodorsal tegmentum
- Nucleus Basalis
- Magnocellular forebrain
2
Q
where does the PPT and LD cell groups for ACh project to
A
thalamus
3
Q
where does the nucleus basalis project to
A
cortex
(or hippocampus)
4
Q
2 main types of ACh receptor
A
- nicotinic
- muscarinic
5
Q
nicotinic ACh receptor
A
- excitatory/ fast
- within cys-loop receptor superfamily
- pentameric
- 16 subunits
- ion channel
- 2+ ACh binding sites
- agonists: nicotine, suxamethonium
- antagonists: atracurium, tubocurarine
6
Q
muscarinic ACh receptor
A
- inhibitory or excitatory/ slower
- monomeric
- family A GPCRs
- 5 subtypes
- binding site for G protein
- 1 ACh binding site
- agonists: muscarine, pilocarpine
- antagonists: astropine, hyoscine
7
Q
roles of ACh
A
- arousal, learning, memory
8
Q
pontine nuclei + ACh
A
- arousal, sleep/wake
9
Q
magnocellular forebrain + ACh
A
arousal
10
Q
septohippocampal + ACh
A
learning (short term memory)
11
Q
striatal internuerons + ACh
A
motor control
12
Q
how is ACh synthesis
A
from AcetylCoA + Choline
via choline-acetyltransferase
13
Q
cholinergic terminal + termination
A
- ACh synthesised
- vesicular release
- signal terminated by AChE (acetylcholineesterase)
- yields choline + acetate
- choline back into nerve terminal
14
Q
cholinergic synapse 1: skeletal NMJ: nicotinic
A
- PNS
- Ca dependent vesicular release
- ACh produces muscle contraction by activating post-synaptic receptors
- AChE termination
15
Q
Neuronal nicotinic receptor synapse for ACh
A
- CNS
- nicotinic receptors found on pre-synaptic nerve terminals or outside the synapse
- act as modulatory role for ACh from neighboring synapses
- activation triggers Ca release / voltage gated Ca channels
- nicotinic receptors modulate release of other neurotransmitter e.g. dopamine, GABA, glutamate
16
Q
muscarinic synapse in CNS and sub-type functions
A
- M2/4 to Gi (dec. cAMP)
- M1/3/5 Gq (PLC activation, inc. Ca via PKC)
- can be post-synaptic AND pre-synaptic (M2)
17
Q
nAChR topology
A
- high permeability to Na+ and K+ (some Ca2+)
- 4 TMDs
- large N terminal (agonist binding site)
- large loop between N3 and N4 (regulator site for enzymes)
- N2 is channel lining
18
Q
muscarinic receptor topology
A
- 7 TMD (GPCRs)
- agonist binding site at top of TMDs
- interaction site for G protein at inner face of receptor
19
Q
Muscarnich ACh sub-types slide
A
20
Q
Darifenacin
A
- best selective antagonist at muscarinic receptors
- M3 selective
- for overactive bladder
21
Q
M currents
A
- by altering this current we can produce excitatory effects
- M current from PIP2 dated K+ channels
- hyperpolarises cell, stabilises RMP so harder to excite
- activation of M1,3,5 (Gq) leads to depletion of PIP2 as cleaved by PLC
- shuts off M current
- cell more excitable
22
Q
What amino acid occludes the nicotinic receptor channel when it is in the closed state?
A
Leucine from M2
23
Q
Which subtypes of the nicotinic receptor is thought to be closely involved in nicotine addiction?
A
2(α4)3(β2)
24
Q
agonists at which receptor may be useful in treatment of schizophrenia
A
M1
- but also in periphery so may cause problems
- and difficult to develop selective agonists for mAChR subtypes
- better to use allosteric modulator
25
In muscarinic receptors, where is the agonist binding domain located?
At the tops of transmembrane domains 3, 5,6,7
26
where is histamine found
- mast cells in the brain (not neurotransmitter: signalling molecule)
- magnocellular neurons in posterior hypothalamus in the brain
27
histamine synthesis and metabolism
synthesis:
histadine -> histamine
via histidine decarboxylase
metabolism:
histamine -> inactive metabolites
via N-methyltransferase (HNMT) and monoamine oxidase (MAO)
28
histaminergic synapse
- H2 (Gs) (post)
- H3/4 (Gi) (post
- H1 (Gq) (post)
- H3 (pre: autoreceptor)
-HNMT modify in synapse for termination ?
29
what histamine receptors are found in the brain vs periphery
H4 - periphery
H1,2,3 - brain
30
H1 antagonists
theraputic uses
e.g. allergy, stings
anti-histamine
- some cross BBB and produce sedation effect (chlorphenamine, triprolidine)
31
H2 receptors
therapeutic uses for ulcer treatment
- not much BBB penetration
32
neuropeptides
- proteins synthesised in the soma
- often produced as pro transmitter to be cleaved to final product in terminal
- vesicular calcium dependent release
- post-synaptic action on GPCRs
- neuro-modulators
- co-transmitters (co-exist with other classical transmitters)
33
the main endogenous opioid peptides
- enkephalins, endorphins, dynorhins
34
Purines
- adensione
- neurotransmitter/ neuro-modulator
- anti-dysrhythmic agent
- NOT vesicular release
- GPCR action: form dimers with other family GPCRs
- stabilise over-activity?
- caffeine as adenosine receptor antagonist (A2A highest affinity)
35
melatonin
- N-acetyl-5-methoxytryamine
- made in pineal gland from 5-HT
- MT1 and MT2 GPCR receptors in brain and retina
- secretion driven by circadian light cycle
- target for anti-jet lag drugs and ant-depressants
36
Nitric oxide
- organic nitrate, can be used to treat angina
- produced by enzyme NO synthase, controlled by Ca++ levels
- inhib. and excit. - cGMP?
- not synaptic ! as it is a gas, rather volume action
- co-transmitter e.g. ACh
- role in LTP/LTD + neurotoxcicity
37
lipids
- derived from arachidonic acid
e.g.prostoglandins, leukotrienes, endocannabinoids
38
endocannabinoids
- act on CB1, CB2 receptors (CNS and PNS)
- 2 main EC's:
1. anandamide
2. 2-arachidonoyl glycerol (2-AG)
- synthesised from membrane lipids
- termination: endocannabinoid membrane transporter (EMT)
- modulatory role
39
production of endocannabinoid
- e.g. in a glutametergic synapse
- activation of mGluR receptors can leads to production of endocannabinoids
- due to stimulation of cleavage of membrane lipids and release of aracadonic acid
- move into synapse
40
3 ways endocannabinoids interact in synapse
- CB1 receptors on post-synaptic membrane: autocrine transmission
- CB1 on pre-synaptic nerve terminal: retrograde tansmission (post to pre)
- coupled to Gi, reduce cAMP via AC, reduce production and release of Glu
- endocannabinoids leak out of synapse, CB1 on pre nerve terminal do same thing on a different receptor e.g. GABAnergic synapse : paracrine transmission
41
which transmitter may act via altering cGMP levels (not cAMP)
NO
42
melatonin receptor agonist
agomelatine
- targets MT1 more than MT2 to treat depression
43
how many histamine receptors found in the brain
3
(1 in periphery)
(4 overall in body)
44
what does lean consist of
codein and promethazine
45
how does lean produce euphoria
codeine at opiod receptors
46
how does lean produce sedation
promethazine at histamine H1 receptors
