Signalling Flashcards
1
Q
what breaks down ACh?
A
AChE, acetylcholinesterase
2
Q
What are the two types of cholinergic signalling?
A
Ionotropic/nicotinic (nAChR) and msucarinic (mAChR)
3
Q
what is the enzyme that forms ACh?
A
ChAT, choline acetyltransferase
4
Q
Antagonist of nAChRs?
A
curare (plant based toxin)
5
Q
what are nAChRs permeable to?
A
Na+, K+ and highly variable to Ca2+
6
Q
whats the role of ACh in somatic nervous system?
A
-voluntary control of body movements
-some reflexes
-NMJ
7
Q
How is ACh involved at NMJ?
A
-ACh activates nAChRs on motor plate (only pass Na+ and Ca+
- eEPP (excitatory end plate potential)
- when eEPP reaches threshold voltage gated Na+ channles open and causes motor end plate AP
8
Q
Name 2 toxins that are competitive antagonists for nAChR?
A
Tubocurarine
A-bungarotoxin
9
Q
Name a AChE inhibitor and how does it work?
A
Physostigimine
- get depolarising block (desensitisation of receptors and deactivated voltage gated Na+ receptors
- used in operative care as a relaxant
10
Q
Name two toxins that block ACh release?
A
Tetanus toxin
Botulinum toxin (both cause paralysis)
11
Q
how is nAChRs involved in myasthenia gravis?
A
-autoimmune (antibodies against nAChRs)
- causes muscle weakness and paralysis
-causes membrane attack complex (MAC) which causes internalisation of nAChRs from membrane
12
Q
Treatment for myasthenia gravis?
A
Neostigmine (AChE inhibitor) and immune system suppressants
13
Q
what are the pathways of the trisynaptic circuit of the hippocampus?
A
Perforant pathway (Entorhinal cortex to dentate gyrus)
Mossy fibres (dentate gyrus to CA3)
Schaffer collaterals (CA3 to CA1)
14
Q
What are the 4 basic properties of LTP?
A
- cooperative (number of fibres simultaneously activated
- input specific (synapse must be activated during induction)
- associative (induction at concurrently active synapses)
- Hebb’s law (spike-timing dependent plasticity)
15
Q
What are the mechanisms underlying LTP?
A
- NMDA receptor dependent
- prolonged depolarisation and alleviation of Mg2+ block (can be associative)
- large fast increase in Ca2+
- Kinase activation (calcium calmodulin kinase)
- insertion of AMPAR
- retrograde signalling (presynaptic changes)
16
Q
what can LTP induction be blocked by?
A
Ca2+ chelators
17
Q
what are some of the mechanisms that contribute to increased AMPAR activity?
A
- changes in protein phosphorylation
- AMPAR properties and trafficking
- cytoskeleton reorganization (remodelling of dendritic spines)
- local protein synthesis (gene transcription via CREB)
18
Q
what can LTD be induced by?
A
prolonged low frequency stimulation
19
Q
what does LTD involved?
A
- internalization of AMPAR
20
Q
how is AMPAR internalized in LTD?
A
- small and slow increases in Ca2+
- phosphatase activation
- dephosphorylation of stargazin and endocytosis of AMPAR
21
Q
what is the induction of LTD (but not LTP) sensitive to?
A
phosphatase inhibitors
22
Q
LTD in the cerebellum?
A
- paired stimulation of climbing fibres and parallel fibres causes LTD that decreases purkinje cell EPSP and acts as a corrective mechanism
- associative (both climbing fibres and parallel fibres must be activated at the same time
23
Q
Mechanism of LTD in cerebellar?
A
- Glu release from parallel fibres activated mGluR
- climbing fibres activation depolarises purkinje cells and voltage gated calcium channels open (increase Ca2+)
- causes synergistic activation of PKC (and MAPK)
- internalisation of AMPAR
24
Q
What is different about electrical synapses compared to chemical?
A
- electrical synapses can flow backwards
25
what are the myelinating cells of the CNS?
oligodendrocytes
26
what do oligodendrocytes do?
provide metabolic support for aoxns
27
differences between oligodendrocytes and Schwann cells?
- Schwann cells are PNS, oligos are CNS
- Schwann cells myelinate a single/single bundle of axons whereas oligos can myelinate multiple axons
28
components om myelin sheath?
70% lipid, 30% protein
29
what are microglia?
resident immune cells of CNS
30
different states of microglia?
'resting'- highly ramified, motile processes to survey environment
'activated'- retract processes, become amoeboid and motile
31
roles of microglia?
- immune surveillance
- phagocytosis
- synaptic pruning
32
which microglia are good and which are bad?
M2 and good
M1 are bad
33
functions of astorcytes?
- developmental (radial glia)
- structural (brain micro-architecture)
- envelope synapses (tripartite synapse, buffer K+ etc.)
- metabolic support (glutamate-glutamine shuffle)
- neurovascular coupling
34
what are MND symptoms due to?
- loss of microglia
- MND spinal cord shows decreases in motor neurons, and increases in microglia and astrocytes
35
definition of commissures?
tracts that cross midline
36
difference in PNS and CNS terminology for cell bodies?
- nuclei in CNS
- ganglia in PNS
37
what drives depolarization?
- influx of Na+
38
what drives repolarization?
- closure of Na+ and opening of K+
39
what drives hyperpolarization?
- voltage gates K+ channels remain open after the potential reaches resting level
40
what is the relative refractory period?
- possible to instigate AP but harder due to hyperpolarization so need even stronger stimulus
- VGSC need time to rest after conformational changes
- confers directionality
41
when does active conduction occur?
- when stimulus is above threshold
42
why is local passive flow important?
-during AP propagation
43
role of cholinergic signalling?
- septal and basal ganglia
- consolidation of memory (AD)
- neocortex (tonically active during 'awake' state on EEG
44
role of serotonin in signalling?
- raphe nuclei of midbrain, pons and medulla
- largest territorial distribution of any set of CNS neurons
- role in depression (SSRIs etc.)
45
role of dopaminergic signalling?
- midbrain DA neurons (substantia nigra (part of BG) and mesolimbic)
- limbic system
- role in SZ
46
role of norepinephrine?
- locus coeruleus in midbrain
- depression (MAOs work on this system)
47
what can inhibit Na+/K+ ATPase?
cardiac glycosides digoxin and ouabain
48
Whats the target of some anti-epileptic drugs such as lamotrigine?
Nav channels
49
Sodium channelopathies?
- epilepsy, migraine, autism, episodic ataxia, pain insensitivity and extreme pain disorders
50
Potassium channelopathies?
- epilepsy syndromes
- episodic ataxia type 1
51
Calcium channelopathies?
- episodic ataxia type 2
- childhood absence epilepsy
- X-linked congenital stationary night blindness
52
what does the gap junction GJB1 (Cx32) cause?
Charcot Matie-tooth neuropathy X linked 1
53
what does gap junction GJC2 (Cx47) cause?
-leukodystrophy, hypomyelinating, spastic paraplegia (non-fatal MND)
54
criteria for NT?
- present in presynatpic neuron
- released in response to depolarisation of presynaptic neuron and release must be Ca2+ dependent
- specific receptors must be present on postsynaptic cell
55
small molecule NT?
amino acids (Glu, Gly), ACh, ATP (dopamine and 5HT), GABA
- short term effects
56
peptide NT?
substance P, vasopressin, CRH, ACTH, opioids and neuropeptide Y
- longer term effects
57
what toxins target SNARE proteins?
-BoTX, botulinum (mainly affects peripheral and visceral neuromuscular synapses and causes weakness)
- TeTX, tetanus (mainly affects inhibiotry spinal interneurons)
58
Models for synaptic vesicle recycling?
- clathrin mediated endocytosis (slow and distal to release site)
- ultrafast endocytosis (very fast and distal to release site, needs dynamin and does not need clathrin)
- kiss and run (fast and at release site)
59
strategies for upregulation of NT?
- supplement NT or precursor (eg. LDOPA in PD)
- inhibit cleafrnace by transporters (eg. SSRIs like prozac in depression)
- inhibit breakdown (eg. AChE inhibitors)
60
strategies for down regulation of NT?
- presynaptically (eg. local application of botox)
- postsynaptically (eg. block receptors with antagonists of receptors; antipsychotics, D2 dopamine receptors)
61
what does ionotropic mean?
- ligand gated ion channels
62
GABAa ionotropic agonists?
- used as sedative, anxiolytics, antoconvulsants and anaestheitc
- Barbiturates activate
- benzodiazepines enhance
63
GABAa ionotropic antagonists?
- Picrotoxin PTZ used experimentally as convulsants (animal models of epilepsy)
- BZD
64
GABAb metabotropic agonist?
- Baclofen
- spasticity in MND and MS
65
GABA reuptake inhibitors?
- tiagabine/gabitril
- used for focal seizures
66
what does glycine work on?
ionotropic Cl- channels
67
what are ionotropic Cl- channles inhibited by?
strychnine (induces seizures)
68
what is ATP castabolised by?
adenosine
69
receptors for ATP?
-P2X (ionotropic receptors)
- P2Y (metabotropic receptors)
- P1 (adenosine)
70
what is the nigrostriatal pathway used for?
movement
71
what is the mesolimbic projection pathway used for?
reward/addication
72
what is the mesocortical projection pathway used for?
- cognition/emotion/motivation
73
MAO-B inhibitors and use?
-selegiline and rasagiline
- use din early PD
74
COMT inhibitors and use?
- entacapone and tolcapone
- used with Levodopa in PD
75
what is noradrenaline used for?
- sleep, wakefulness and attention
76
what type of receptors are adrenergic receptors?
- metabotropic
77
inhibitors of adrenergic receptors and use?
- beta blockers eg. propranolol used to treat cardiac arrhythmias and migraines
78
role of histamine?
arousal and attention
79
antihistamines?
- cross BBB
- promethazine (blocks H1) acts as a sedative
80
role of serotonin?
mood, sleep, wakefulness, nausea and appetite
81
therapeutic role of serotonin?
- SSRIs (fluoxetine and prozac)
- sumatriptan (agonist of 5HT1) helps with migraines
- atypical antipsychotics are antagonists of 5HT2
- ondansetron is antagonist on 5HT3 (reduces nausea and vomitting in chemotherapy)
82
what can excess serotonin cause?
- serotonin syndrome
- shivering and diarrhoae (mild)
- rigidity, seizures and fever (severe)
83
role of serotonin in PD?
- loss of serotonergic neurons
84
peptide NT involved in pain?
substance P and opioid peptides
85
peptide NT involved in stress repsonse?
CRH/CRF
86
peptide NT involved in food intake?
NPY and melanocortins
87
pituitary peptides?
- vasopressin and oxytocin
88
sources of presynaptic glutamate?
- reuptake through glutamate transporters
- conversion of a-ketoglutarate to glutamate
- conversion of glutamine to glutamate via glutaminase
89
what is the most abundant excitatory NT in the brain?
glutamate
90
ionotropic glutatamate receptors?
- ligand gated
- postsynatpic receptors
- fast
- excitatory
91
agonist and antagonist of ionotropic glutamate receptors?
agonist: glutamate
antagonist: kynurenic acid
92
types of ionotropic glutamate receptors?
NMDA, AMPA, Kainate
93
metabotropic glutamate receptors?
- GPCR
- post and presynaptic
- can be excitatory or inhibitory
94
what is AMPA receptors permeable to?
- Na+ and K+
- can be permeable to Ca2+ but generally not common
95
what does NMDA receptor need?
- coagonist glycine
96
what are NMDA receptors permeable to?
K+, Na+ and Ca2+
97
what are NMDA receptors blocked by?
Mg2+ channel block
98
difference between NMDA and AMPA receptors?
- NMDA has slower kinetcs and holds onto glutamate longer than AMPA
- AMPA has quick binding and unbinding of glutamate
99
role of AMPA and NMDA in LTP?
- glutamate binds to both receptors
- NMDA blocked due to Ca2+
- AMPA causes partial depolarisation (open NMDA coincidence detector
- NMDA now permeable to Ca2+
- Ca2+ influx initiate signalling cascades (calmodulin and activation of CAM kinase II)
- promotes recruitment of AMPA receptors to postsynaptic membrane
- more AMPA receptors menas can repsonse with greater strength to sam eamount of glutamate
100
glutamatergic signalling and excitotoxicity?
- excessive glutamate receptor activation can lead to activation of signalling cascades that promote cell death
- driven by excessive calcium mediated signalling
101
ways in which excessive calcium mediated signalling can drive excitotoxicity?
- mitotoxicity (increased reactive oxygen species)
- apoptosis via caspase-3 induction
-nitrous oxide synthase (nNOS) increase mitochondrial permeability transition pore function leading to solute overload and mitochondrial swelling
102
what are NMDA recepotrs involved in?
- synapse to nucleus signalling
- regulation of transcription
- function of target genes: dendrite maintenance, protection of mitochondria, acquires neuroprotection, consolidation of plasticity
103
ALS and glutamate?
- glutamate induced motor neuron death is a hypothesis of disease progression of ALS
- hyperexcitability suggests to be be pre-symptomatic feature or early feature of ALS progression
104
what does tetradoxin block?
Na+ channels
105
what does tetradoxin block?
Na+ channels
106
what does tetraethylammonium (TEA) block?
K+ channels
107
what do cardiac glycosides digoxin and ouabain block?
Na+/+ ATPase
108
what does lamotrigine target?
Nav channels
109
Potassium channel blockers?
-fampridine/ampyra
- amiadarone
110
agonist of TRPA1 channel?
- mustard oil
-
111
agonist of TRPM8 channel?
- menthol
112
agonist of TRPV1 channel?
- capsaicin (pain)
- histamine (itch)
113
agonist of TRPV4 channel?
- serotonin
- histamine
