Neurotransmission Flashcards
1
Q
What is neurotransmission?
A
The process by which neurons communicate with one another across synapses using neurotransmitters (endogenous chemical messenger)
2
Q
What is the resting membrane potential of a neuron
A
-70mV
3
Q
What is the function of the Na+/K+ ATPase pump?
A
Uses energy from ATP to move out 3 Na+ ions and move in 2 K+ ions against their concentration gradient
4
Q
What is the function of potassium leak channels?
A
move K+ ions out of the cell down its concentration gradient
5
Q
A- proteins are permeable and can leave the cell. True or false
A
False
Impermeable, cannot leave the cell
6
Q
How is the resting membrane potential of a neuron kept negative?
A
- Na+/K+ ATPase pump
-potassium leak channels - A- proteins
7
Q
Briefly state the stages of an action potential
A
- Resting potential
- Depolarization (threshold potential)
- Repolarization
8
Q
What is the threshold potential of neurones ?
A
-55mV
When the threshold potential is reached an all or nothing action potential is fired
9
Q
During repolarisation, hyperpolarisation briefly occurs. Describe hyperpolarisation.
A
Hyperpolarisation is also known as the refractory period. At this point no other action potential can be reached.
During hyperpolarisation, the membrane potential goes past -70mV however gradually over time ion concentrations return to resting levels and the membrane potential returns to -70mV
10
Q
What is an inhibitory post synaptic potential (IPSP)?
A
a temporary hyper-polarization of the post synaptic membrane caused by flow of negatively charged ions (e.g. Cl-) into the post synaptic cell
11
Q
What is an excitatory post synaptic potential (EPSP)?
A
these are synaptic inputs that induce depolarisation of the membrane, bringing potential to the threshold potential and closer to firing the action potential
12
Q
What is the result of an action potential in a neuron?
A
release of neurotransmitters
13
Q
What are the classifications of main neurotransmistters?
A
Amino acid
Monoamines
Peptide
14
Q
Amino acid neurotransmitters are able to carry out most functions. Give examples of amino acid neurotransmitters.
A
Glutamate
GABA
Glycine
15
Q
What are the main functions of monoamine neurotransmitters?
A
Attention
Cognition
Emotion
16
Q
Give examples of monoamine neurotransmitters
A
Serotonin
Histamine
Dopamine
Adrenaline
Noradrenaline
17
Q
What is the main function of peptide neurotransmitters?
A
Pain
18
Q
Give examples of peptide neurotransmitters
A
Opioids (endorphins)
19
Q
“Other” neurotransmitters include acetylcholine. Briefly state some functions of this neurotransmitter
A
Autonomic nervous system
Motor nerves
20
Q
How is glutamate synthesized?
A
glutamate can be generated from glutamine by the action of glutaminase in the mitochondria
glutamate can also be generated by the transamination of aspartate or alanine
21
Q
Glutamate is stored in the synaptic vesicles and released following __________.
A
Ca2+ (calcium ion) influx
22
Q
How is glutamate metabolised?
A
Glutamate is primarily takend up by GLT-1 and GLAST transporter proteins located on adjacent glial cells
The glutamate is converted into glutamine in the glial cells
Glutamine is then taken back up by neurones and is converted in the mitochondria to glutamate
Some neurones also express EAAC1 which recycles glutamate directly
23
Q
Glutamate receptor are ________ receptors. What kind of receptors are they?
A
Ionotrophic and metabotropic
24
Q
Describe the structure of glutamate receptors
A
Form tetrameric complexes with a central pore
each subunit consists of a transmembrane domain, ligand binding domain and an extracellular N terminal domain
25
Give examples of glutamate receptors
NMDA
AMPA
Kainate
26
What is required for NMDA activation ?
Simultaneous binding of glutamate and glycine neurotransmitters
27
What prevents excessive activation of NMDA receptor ?
magnesium ion blocking the ion channel
Voltage dependent Mg2+ block
28
Briefly describe the permeability of NMDA receptors to Ca2+ ions
Highly permeable
29
NMDA receptors have a slow activation-deactivation (ms) and weak desensitisation. True or false
True
30
What are the possible subunits for an NMDA receptor?
N1-N3
N1
N2
N3
2 N1 subunits present
2 N2/N3 subunits present
31
AMPA glutamate receptors have fast activation- deactivation and strong desensitisation. True or false
True
32
Describe the permeability of AMPA receptors to Ca2+ ions
less permeable
33
What are the possible subunits for AMPA receptors
A1- 4
A1
A2
A3
A4
34
Kainate glutamate receptors constitute ____ possible subunits
5
K1
K2
K3
K4
K5
35
What is thought to contribute to cell death in a number of neurological disorders including alzheimers, huntingtons, parkinsons, stroke and MS?
NMDA-R mediated Ca2+ overload
36
What can be used pharmacologically to combat NMDA-R mediated Ca2+ overload?
Ketamine
Memantine
37
What is ketamine?
a non-competitive open channel blocker
38
Ketamine is licensed for use for...
the induction and maintenance of anaesthesia
may also be useful as an analgesic and in the treatment of major depressive disorder
39
What is memantine?
Non-competitive open channel blocker
40
Memantine is currently used to treat ...
moderate to sever alzheimers
41
Memantine is a ______ affinity NMDA receptor antagonist
low affinity
42
Briefly describe the on and off kinetics of memantine
fast on-off kinetics
43
What is the consequence of AMPA and Kainate receptor over-activation?
glutamate induced neurotoxicity
44
Antagonists of glutamate are _____________. They help reduced ischaemia induced white matter injury.
neuroprotective
45
List drugs that act on AMPA and Kainate receptors
Topiramate
Perampanel
Texampanel
46
Topiramate inhibits which receptors? What is its clinical use?
inhibits both AMPA and kainate receptors
licensed for use as an adjunct for epileptic seizures and prophylaxis of migraine
47
What is perampanel?
A highly selective non competitive AMPA antagonist
48
What is the current clinical use of perampanel ?
adjunct for epileptic seizures
49
Tezampanel is more selective for which receptor?
Kainate receptor
50
What is the current clinical use of tezampanel?
currently being investigated for treatment of migranes
51
Where is the glutamate binding site on metabotropic glutamate receptors?
between the two lobes of the VFT domains
(venus fly trap)
52
Where are metabotropic glutamate receptors primarily located?
presynaptically
53
Metabotropic glutamate receptors play an important role in _________.
Long term depression (LTD)
54
Metabotropic glutamate receptors are grouped into 3 classes. What are group I metabotropic receptors ?
mGlu1 and mGlu5
Gq linked to PI-PLC pathway (phosphoinositide- phospholipase C)
55
Metabotropic glutamate receptors are able to form ___________ structures
heterodimeric
56
mGlu5 antagonists are thought to...
reverse intellectual disability
Fragile X syndrome
57
What is the function of metabotropic glutamate receptors?
they have been known to modulate the activity of other receptors e.g. modulation of NMDA-R
58
What receptors/variants are in group II mGLuRs ?
mGlu2
mGlu3
59
Group II and III mGluRs are linked to...
Gi- inhibition of adenylate cyclase
60
What receptors/variants are in group III mGluRs?
mGlu4
mGlu6
mGlu7
mGlu8
61
Positive modulators of group II mGluRs are being investigated for ...
schizophrenia
62
Positive modulators of what group III variant is being investigated for treatment of parkinsons?
mGlu4
63
GABA is synthesised from _______ by the action of what enzymes?
Glutamate
Glutamic acid decarboxylase enzyme (GAD)
64
GAD (Glutamic acid decarboxylase enzyme) is comprised of two different molecular weights. What are the molecular weights?
65kDa
67kDa
65
What is the major isoform of GAD enzyme in the brain?
GAD65
66
The majority of the GAD65 isoform is inactive. True or false
True
67
During metabolism of GABA, the majority of GABA is taken up by ______ in _________ and repackaged.
GABA transporters- GAT
in Presynaptic terminals
68
What enzyme catabolises GABA to glutamine ? Where is this enzyme found?
GABA transaminase (GABA-T)
found in glial cells
69
GABA ionotropic receptos belong to what family of receptors? What do they form?
Cys- loop family of receptors
They form pentameric complexes with a central pore
70
Each subunit of GABA ionotropic receptors consists of...
Extracellular ligand binding domain
Transmembrane domain with 4 transmembrane alpha helices
71
GABAa ionotropic receptor is permeable to what ion?
Chloride
72
GABAa receptors are assemblies of what subunits?
alpha 1-6
beta 1-4
gamma 1-4
delta
epsilon
pie
theta
rho
73
GABAa receptors are usually composed of 5 subunits. What are the most common subunits for a GABAa receptor?
2alpha
2 beta
1 gamma
74
How many binding sites for GABA are present on a GABAa receptor? What are there referred to as?
2
alpha-beta interface
75
GABAa receptors also contain a benzodiazepine site to enable benzodiazepine binding. What is this referred to as?
alpha- gamma interface
76
GABAc ionotropic receptors are chloride permeable ion channels that are composed entirely of _____ subunits.
Rho subunits
77
Where are GABAc ionotropic receptors expressed?
Expressed exclusively in the retina
78
GABAa receptors are allosterically modulated by what chemicals/compounds?
Benzodiazepines
79
An example of a benzodiazepine is...
Diazepam
80
What subunits are important in benzodiazepine binding to GABAa receptors?
Alpha 1,2,3 AND 5
Beta
Gamma 2
81
Benzodiazepines are useful in the treatment of...
seizures
anxiety
insomnia
alcohol withdrawal
muscle spasms
82
What subunit of GABAa receptors mediates the sedative effects of benzodiazepines?
Alpha 1 subunits
83
What subunits of GABAa receptors mediate the anxiolytic effects of benzodiazepines?
alpha 2 and 3
84
What is the effect on barbiturates on GABAa receptors?
they can stimulate channel opening independent of GABA binding at a concentration >50uM
85
An example of a barbiturate used to treat epilepsy is...
Phenobarbital
86
An example of a barbiturate that is used as an anaesthetic is...
Thiopental
87
What is the effect of steroids such as progesterone derivative on GABAa receptors ?
they are able to open the channel directly
at a concentration >50uM
88
What progesterone derivative is in trials for treatment of epilepsy?
Ganaxolone
89
Anaesthetics such as propofol and etomidate allosterically modulate GABAa receptors. Their action is thought to involve what subunit?
Beta 3 subunit
90
What are the two isoforms of GABAb receptors?
GABAbR1
GABAbR2
91
The isoforms of GABAb receptors are only able to form functional receptors when they are...
dimers
92
GABAb receptors are ________ receptors. What is their function
Metabotropic receptors (GPCRs)
their function is to modulate ion channel activity
93
What is the function of pre-synaptic GABAb receptors?
to reduce multi-vesicular release of glutamate (inhibit VGCC)
inhibition of voltage gated calcium channels- preventing influx of calcium ions
94
What is the function of post synaptic GABA receptors?
to reduce neuronal excitability by enhancing K+ channel activity and reducing Ca2+ channel activity through Gbetagamma subinits (G protein beta and gamma subunits)
95
GABAb receptors have also been linked to the inhibition of adenylal cyclase enzyme through the action of what proteins?
Gi proteins
96
What is baclofen?
an agonist for GABAb receptors
used as a skeletal muscle relaxant and used to treat severe chronic spasticity
97
Where is glycine found?
spinal cord and brain stem
98
What physiological functions is NT glycine involved in?
reflex responses
processing sensory signals
pain sensation
99
What is the predominant trasnsporter in presynaptic terminals of glycinergic neurones?
GLYT2 transporter
100
What is the predominant glycine transporter in glial cells?
GLYT1 transporters
101
Glycine can be metabolised by ______
glycine decarboxylase system
102
Glycine receptors belong to what family?
Cys-loop ligand gated ion channel
103
Glycine receptors are permeable to ____ ions which lead to __________.
Cl-
hyperpolarisation
104
What subunits have been identified to form glycine receptors?
Four alpha subunits
One beta subunit
105
Inherited mutations to the human Glycine receptor genes give rise to what condition?
Hyperekplexia
An exagerrated surprise/pronounced startle: newborns
106
RG1678 is a __________. It is currently in clincial trials for the treatment of ___________.
GLYT1 (glial cells) inhibitor
Schizophrenia
107
Briefly state the synthesis of Dopamine
L-tyrosine ---> L-DOPA --->Dopamine
108
What enzymes are involved in the synthesis of dopamine
Tyrosine hydroxylase
DOPA decarboxylase
109
Dopamine can be removed from the synaptic cleft by...
Dopamine transporter (DAT)
Noradrenaline transporter (NET)
110
What are the 3 enzymes that are involved in the metabolism of dopamine?
Monoamine oxidase A (MAO-A)
Monoamine oxidase B (MAO-B)
Catechol-O-methyl transferase (COMT)
111
Where are MAO-A enzymes located?
Mitochondria
112
MAO-A metabolises what monoamines?
Dopamine
Noradrenaline
Histamine
113
MAO-B metabolises ...
Dopamine
114
COMT enzymes are widely distributed. What are they responsible for metabolising?
All cathecholamines
Dopamine
Noradrenaline
Adrenaline
115
Dopamine receptors are metabotropic 7 TM GPCRs which are involved in ...
Locomotor activity
Reward and reinforcement
Learning and memory
Psychosis
116
What dopamine receptors are involve in locomotor activity ?
D1
D2
D3
117
What dopamine receptors are involved in reward and reinforcement?
D1
D2
118
What dopamine receptors are involved in learning and memory?
D1
D2
119
What dopamine receptors are involved in psychosis?
D2
120
Dopamine receptors are subdivided into D1- like and D-2 like receptors. What are the D1-like receptors
D1
D5
121
D1-like dopamine receptors are linked to what type of G protein?
Gs linked
D5 receptors also linked to Gq proteins
122
D1 receptor expression is found in what areas?
Nigrostriatal
Mesolimbic
Mesocortical areas
123
D2 like receptors are ________. What kind of G proteins are they linked to ?
Inhibitory
Gi
124
D2 like dopamine receptors include...
D2
D3
D4
125
D2 receptors are expressed in...
striatum
nucleus accumbens
olfactory tubercle
126
D3 dopamine receptors are expressed in ...
limbic areas
127
D4 dopamine receptors are lowly expressed in ...
the CNS
128
Enhanced ____ sensitivity is observed in schizophrenia
D2
129
Dopamine receptors are involved in...
wakefulness (arousal)
mood
emotion
130
Dopamine receptors also have a role in the secretion of what hormone?
prolactin
hormone involved in lactation (milk production)
131
What is the functional role of dopamine receptors in the cortex?
arousal
mood
132
What is the dominant D1 like type dopamine receptor in the cortex?
D1
133
What D1 and D2 dopamine receptors are absent in the cortex
D5 (D1 LIKE)
D3 (D2 like)
134
What is the functional role of dopamine in the limbic system?
Emotion
Stereotypic behaviour
135
All D1 and D2 types of dopamine receptors are present in the limbic system. True or false
True
136
List some agonists for dopamine receptors
Apomorphine
Bromocriptine
Ropinirole
137
What is apomorphine?
non selective dopamine agonists used to treat parkinsons disease
138
What is bromocriptine?
D2 agonist used to treat parkinsons disease and endocrine disorders such as acromegaly
139
What is acromegaly ?
endocrine disorder where the body produces too much growth hormone
140
What is ropinirole?
D2 like receptor agonist (D2, D3 D4) used to treat parkinsons disease and restless leg syndrome
141
Give an example of a 1st generation antipsychotic which is a D2 receptor antagonist
Haloperidol
142
Give an example of a 2nd generation antipsychotic drug which is a D2 receptor antagonists
Clozapine
143
What are anti-emetic drugs?
Anti-sickness drugs
prevent nausea and vomiting
144
Domperidone is an anti-emetic drug that blocks ______ receptors in the _________
D2 and D3 receptors
in the chemoreceptor trigger zone (CTZ)
145
Metoclopramide is an anti-emetic that primarily blocks which dopamine receptor?
D2 receptor
146
Give examples of dopamine antagonists that are used to treat depression and schizophrenia?
Flupentixol
Quetiapine
Affect multiple dopamine receptors
147
Briefly state the synthesis of noradrenaline
L-tyrosine --> L-DOPA --> dopamine --> noradrenaline
148
The synthesis of noradrenaline utilises which enzyme?
Dopamine B-hydroxylase
149
How is noradrenaline removed from the synaptic cleft?
Noradrenaline transporter (NET)
150
What enzymes are involved in the metabolism of noradrenaline?
MAO-A
COMT
151
Noradrenaline alpha receptors are ______ receptors
Metabotropic GPCRs
7TM GPCRs
152
Where are Noradrenaline alpha receptors primarily expressed?
smooth muscle in the periphery
153
What is prazosin?
it is a noradrenaline a1 specific blocker used to treat hypertension and congestive heart failure
154
What are the characteristics of a1 noradrenaline receptors
Ga linked
3 subtypes (1a, 1b and 1d)
155
Noradrenaline a1b receptor has been suggested to be involved in ...
addiction
seizures
neurodegeneration
156
What are some characteristics of a2 noradrenaline receptors?
Gi linked
2a, 2b and 2c
157
What is the function of alpha2 noradrenaline receptors
act as autoreceptors inhibiting the release of various neurotransmitters
158
What are agonists of alpha 2 noradrenaline receptors used for?
used to treat recurrent migraines and alcohol withdrawal symptoms
159
Give an example of a alpha 2 noradrenaline receptor agonist
Clonidine
160
Beta receptors of noradrenaline are also 7 TM GPCRs. What G proteins are they associated with?
Gs proteins
161
Antagonists of noadrenaline Beta receptors have been licensed for the treatment of which conditions. Give examples of a drug for each condition.
Anxiety- propanolol
migraines- nadolol, timolol
hyperthyroidism- metoprolol
162
What is the function of B1 noradrenaline receptors
Retrieval of contextual and spatial memories but not emotional memories
163
Acute stress can impair memory retrieval through B2 receptors. True or false
True
164
Noradrenaline activated neurogenesis in hippocampal neurones through which noradrenaline receptor?
B3 receptor
165
How is serotonin (5HT) synthesised?
from tryptophan (Trp)
transported into the brain utilising a neutral amino acid carrier
166
What enzymes are involved in synthesis of 5HT
Trp --> 5-hydroxytryptophan (5HTP) by tryptophan hydroxylase
5HTP---> 5HT (hydroxytryptamine) by aromatice amino acid decarboxylase (AADC)
167
How is 5-HT taken up into vesicles ?
by vesicular monoamine transporter-2
168
How is 5-HT taken back into nerve terminals and glial cells?
Active transport via SERT (serotonin transporter)
169
How is 5-HT metabolised?
MAO-A
170
What physiological processes are 5-HT involved in?
sleep
appetite
thermoregulation
pain perception
171
What disorders is 5-HT involved in?
Migraines
Depression
Psychosis
Drug abuse
172
5-HT4 receptors are ...
Heteroreceptors
173
5-HT6 receptors have ________ locations
heterologous dendritic locations
174
Where are 5-HT7 receptors mainly located ?
soma and axon terminals of GABAergic neurones
175
What 5-HT receptors are Gas linked?
5-HT4, 5-HT6, 5-HT7
176
What 5-HT receptors are Gai linked?
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT1F
177
5-HT1A receptors have both ____ and ____ locations. What is their effect on neuronal firing?
Pre and post synaptic location
inhibit neuronal firing
178
5-HT1B and 5-HT1D are _______. What is their function ?
heteroreceptors
inhibit neurotransmitter release
179
What 5-HT receptors are Gaq linked?
5-HT2A
5-HT2B
5-HT2C
180
5-HT2A receptors have ______ locations. What is their possible function?
somato-dendritic locations
May modulate glutamate release
181
Give examples of antipsychotic drugs which antagonise 5-HT receptors and the receptors they block
Olanzapine - 5-HT2A, 5-HT2C
Quetiapine- 5-HT1A, 5-HT2A
Risperidone- 5-HT2A, 5-HT2C
182
What is buspirone?
partial agonist of 5-HT1A receptor
Licensed for short term treatment of anxiety
183
What are agonists of the 5-HT1B and 5-HT1D receptors? What are they used to treat ?
Triptans
Sumtriptan
Zolmitriptan
Acute migraines and cluster headaches
184
Lorcaserin is a _________ agonist. What is its current clinical use?
Selective 5-HT2C agonist
reduces appetite so being investigated for treatment of obesity
185
Xaliproden is a ________ agonist. What is its proposed clinical use?
5-HT1A agonist
Showed neuro-protection in vivo, investigated for treatment of alzheimers disease
186
What 5-HT receptors are cation selective channels that belong to the ligand gated ion channel family ?
5-HT3 receptors
187
How many 5-HT3 receptors are there? Name them
5
5-HT3A, B, C, D, E
188
5-HT3A subunits can form what kinds of receptors?
Homomeric
Heteromeric receptors (other subunits)
189
Where do 5-HT antagonists bind?
A-A- interface in 5-HT3A/3B receptors
(3A-3A)
190
List some 5-HT3 antagonists
Granisetron
Ondensetron
Palonosetron
191
Granisetron is ...
a selective antagonists used to treat post-operative and chemotherapy induced nausea and vomiting
192
Ondensetron is licensed to treat...
different types of nausea and vomiting
being investigated for neuropsychiatric disorders and alcoholism
193
Palonosteron is a ...
2nd generation 5-HT3 antagonist with higher affinity and longer half life used to treat chemotherapy induced nausea and vomiting
194
How is histamine synthesised?
synthesised from histidine by histidine decarboxylase
195
How is histamine inactivated in the synaptoc cleft?
By neuronal histamine N methyltransferase (HNMT)
196
What are the histamine receptors?
There are 4 TM histamine receptor types
H1R-H4R
197
What histamine receptors are expressed in abundance in the brain?
H1R-H3R
198
What histamine receptors are coupled to Gq proteins ?
H1R
199
H2R histamine receptors are coupled to _____ proteins. What kind of activity do they exhibit?
Gs
Constitutive
200
H3R histamine receptors are coupled to _____ proteins. They have a degree of ______ activity in vivo
Gi/o
constituitive
201
H4R histamine receptors are coupled to what G proteins? Where are they found?
Gi/o
mainly in periphery
202
What histamine receptor has a high degree of similarity to the H3Rs?
H4Rs
203
What is pitolisant ?
inverse H3R receptor agonis
licensed for treatment of nacrolepsy in US
in clinical trials for AD and schizophrenia
204
Acetylcholine is synthesised from _____ by ________.
choline and acetyl CoA
Choline acetyl transferase enzyme (ChAT)
205
How is Ach metabolised in the synaptic cleft?
acetylytransferase enzyme
products taken back up into nerve terminals
206
Acetylcholinesterase is inhibited by drugs used to treat what conditions? Give examples
Alzheimers disease- Donepezil (improves cognition and behaviour)
Myasthenia Gravis- Neostigmine (improves muscle tone)
207
What are nicotinic ACh receptors?
Cation selective channel that belongs to the cys-loop ligand gated ion channel family
208
What is varenicline?
partial agonist of a4B2 nicotinic ACh receptor
full agonist at a7 receptor
licensed for treatment for smoking cessation
under investigation for schozophrenia as an adjunct, cocaine dependence
209
What is bupropion?
non competitive nicotinic receptor antaginist
inhibits DAT and NET (dopamine and noradrenaline transporters)
used as treatment for nicotine addiction
210
ACh muscarinic receptors are...
metabotropic
7TM GPCRs
211
Muscarinic antagonist are used as ...
bronchodilators
Ipatropium
Tiotropium
212
Muscarinic agonists are used to treat _____
glaucoma (pilocarpine)
urinary retention (bethanechol)
213
What are the Gq linked muscarinic ACh receptors?
M1-M3 and M5 isoforms
214
Numerous M1 receptors blockers have been developed and successfully used to treat AD. True or false
False
They are ineffective
215
What muscarinic ACh receptors are Gi linked?
M2 and M4
216
What is the effect of Gi linked receptors?
Lead to inhibition of Adenylyl cyclase
217
What is the effect of Gq linked receptors?
Activation of PLC
IP3 and DAG production
Mobilisation of calcium ions
218
Xanomeline is a muscarinic ACh agonist. What isoforms have a preference for Xanomeline?
M1 and M4
