Neurotransmitters Flashcards
1
Q
Chemical signaling consists of…
A
A molecular signal (neurotransmitter)
* A receptor molecule (transduces information
provided by the signal)
* A target molecule (ion channel) that is altered to
cause electrical response in the postsynaptic cell
(can be the same as the receptor)
2
Q
Criteria that define Neurotransmitters
A
- The substance must be present within the presynaptic neuron.
Problems: Transmitters like glutamate, glycine and aspartate have also other functions in cellular metabolism
and/or function as precursor for other transmitters (e.g. dopamine for norepinephrine, glutamate for GABA). - The substance should be released in response to presynaptic depolarization
(but there are exceptions), and the release must be Ca2+
-dependent. - Specific receptors for the substance must exist on the postsynaptic cell.
3
Q
Three types of small-molecule neurotransmitters
A
- Acetylcholine
- Amino Acids
- Biogenic Amines
4
Q
Two types of Metabolism of Neurotransmitters
A
- Classical (small molecules)
- Neuropeptides
5
Q
“Classical” transmitter
(small molecules)
A
Local synthesis in the
presynaptic terminal.
Synthesizing enzymes come
from nucleus via slow axonal
transport
small clear core vesicles
6
Q
Neuropeptides
A
Synthesis in the soma
(nucleus; rough endoplasmic
reticulum [pre-propeptides]
and Golgi apparatus
(propeptides]).
Complete
vesicles reach terminal via
fast axonal transport
through microtubules
large dense core vesicles
7
Q
Release of neuropeptides requires
A
high frequency stimulation to co-release with small molecule transmitters
→ Importance of calcium levels in the presynaptic terminal
8
Q
Ionotropic Receptors
A
- Membrane spanning region forms ion channel.
- Comprised of 3-5 protein subunits.
- Mediate rapid postsynaptic effects (millisecond time scale)
- Glutamate receptors
(NMDA, non-NMDA) and Cys-loop receptors
9
Q
Cys-loop receptors
A
nicotinic acetylcholine
receptor (nAChR)
* 5-HT3 receptor
* GABAA receptor
* Glycine receptor
* Purinergic receptors
10
Q
nicotinic ACh, GABAa, Glycine receptor channels are
A
pentamers
11
Q
Glutamate receptor channels are
A
tetramers
12
Q
Acetylcholine Precursors
A
Acetyl coenzyme A and choline
13
Q
Enzyme that catalyzes precursors into Acetylcholine
A
choline acetyltransferase
(ChAT)
14
Q
After release,
this breaks up
ACh into acetate and choline
A
Acetylcholinesterase
ACh-esterase is the target of
nerve gases/pesticides
15
Q
A Na+
/choline transporter
takes
A
choline back up into
the presynaptic terminal
16
Q
Irreversible Acetylcholinesterase inhibitors
A
Insecticides (so-called organophosphates), and
nerve gases (e.g. Sarin, Soman)
17
Q
Irreversible AChE-inhibitors completely
A
inhibit ACh breakdown
18
Q
Irreversible Acetylcholinesterase inhibitors
The lethal effect results from
A
“overstimulation” (persistent depolarization) of the
postsynaptic membrane, particularly muscle cells.
19
Q
Irreversible Acetylcholinesterase inhibitors
The main effect is
A
neuromuscular paralysis (leading to respiratory failure within 5
min), preceded by cognitive and severe autonomic symptoms.
20
Q
Irreversible Acetylcholinesterase inhibitors
Treatment involves
A
combined administration of a muscarinic receptor antagonist
(e.g. atropine) and the AChE antagonist pralidoxime, which paradoxically restores
AChE function
(→ Pralidoxime attaches to the site where the cholinesterase inhibitor has attached, then attaches to the
inhibitor, removing the organophosphate from cholinesterase, allowing it to work normally again)
21
Q
Glutamatergic synapse
A
most prevalent excitatory transmitter (>half of all synapses)
22
Q
Precursor of glutamate
A
glutamine
23
Q
Enzyme that catalyzes
glutamate from [precursor]
A
glutaminase
24
Q
VGluT
A
vesicular
glutamate transporter
25
# Glutamatergic synapse
EAAT
excitatory
amino acid transporter
5 different types –
some on presynaptic
terminals, others on
glia cells (→ GLT1,
GLAST)
26
Neurotransmitter
transporters for
re
-uptake
Often use electrochemical
gradients, e.g. co-transport
(symport) of sodium
27
Ionotropic Glutamate Receptors
* NMDA (GluN)
* AMPA (GluA)
* kainate (GluK)
non-selective cation channels
→ Na+, K+, and Ca2+
28
NMDA-R serves as
coincidence detector:
29
# NMDA-R
voltage-dependent block by
Mg2+ ion
needs to be
relieved by depolarization,
→ requires simultaneous
activation of AMPA -Rs
30
# NMDA-R
influx of Ca2+ acts as
second
messenger at intracellular
signaling pathways
→ relevant for synaptic
plasticity.
31
NMDA-Rs require __ as
co-agonist
glycine
32
APV
NMDA antagonist; blocks NMDA-R
so that only AMPA current remains
33
AMPA-R (or GluA) consists of
four homologous pore-forming subunits (GluA1–4), which mostly
assemble into heteromers.
assemblies
| tetrameric
assemblies
34
“Normally”, AMPARs are
not permeable to
Ca++.
35
some AMPARs
either
lack GluA2
subunits (very low permeability to Ca2_), or have an
unedited transcript of
the GluA2 gene (blue)
→ permeable to Ca2+
(CP-AMPA)
36
# mGluRs - metabotropic glutamate receptors
3 groups based on pharmacology and second messenger linkages:
Group I (mGluRs 1 and 5)
Group II (mGluRs 2 and 3)
Group III (mGluRs 4, 6, 7, and 8)
37
Group I (mGluRs 1 and 5)
excitatory, Gq-coupled
(→PLC → ion channels; increase NMDA)
- mostly postsynaptic
38
Group II (mGluRs 2 and 3)
inhibitory, Gi/Go- coupled
(→ reduce cAMP),
decrease transmitter release; decrease NMDA
- mostly presynaptic, and on glia cells
39
Group III (mGluRs 4, 6, 7, and 8)
- inhibitory, Gi/Go- coupled
(→ reduce cAMP), decrease transmitter release;
decrease NMDA
- mostly presynaptic
40
PDZ domains have two main functions:
Anchoring receptor proteins to
cytoskeletal components, and regulating cellular pathways
PDZ domains bind to a short region of the
C-terminus of other specific proteins
41
Some important PDZ proteins are
* PSD-95
* GRIP
* Homer
* Shank
42
# PDZ domain proteins and their associated receptors:
* PSD-95
NMDAR
function as scaffolds at the
postsynaptic membrane
PSD-95 has three PDZ domains:
The first two PDZ domains interact with the C-terminus of
receptors (mostly NMDA) or with Shaker-type K+ channels.
The third PDZ domain interacts with cytoskeleton-related proteins
43
# PDZ domain proteins and their associated receptors:
GRIP
AMPAR
44
# PDZ domain proteins and their associated receptors:
Homer
regulates mGluR signaling.
45
# PDZ domain proteins and their associated receptors:
Shank
crosslinks NMDARs and mGluRs
46
Glutamate receptors
rapidly go in and out of the membrane
move rapidly intracellularly
47
Transmembrane-AMPAR Regulatory Protein (TARP)
auxiliary subunits of AMPARs that modulate expression, channel properties and localization of AMPARs.
4 different TARPs which show partly overlapping distributions
in the brain.
48
Stargazin
Stargazin is dominant in cerebellum
prototypical TARP that acts as an auxiliary subunit that controls both receptor gating and trafficking.
In the membrane, stargazin interacts with PSD-95 to anchor the AMPARs
49
Stargazin
Stargazin is dominant in cerebellum
prototypical TARP that acts as an auxiliary subunit that controls both receptor gating and trafficking.
In the membrane, stargazin interacts with PSD-95 to anchor the AMPARs
50
Homer consists of two major splice variants:
The constitutive long-forms (Homer1b-h, Homer2a or b, and Homer3a or b) and
* the short-form (Homer1a)
51
Long-form Homer proteins bind
the carboxyl terminus of group I mGluRs and IP3Rs, forming an
efficient signaling complex that generates IP3
and releases Ca2+ from intracellular pools.
Long forms are constitutive
52
Homer1a is
nduced by neuronal activity
Homer1a competes with CC
-Homer (long forms) and disassembles the signaling
complex (“uncouples” mGluR signaling
53
the short form of Homer is
considered to be a part of a mechanism of
homeostatic plasticity that dampens the neuronal responsiveness when input activity is too high.
54
The long form Homer1c plays a role in
synaptic plasticity and the stabilization of synaptic changes during long-term potentiation.
55
Shank is required for
proper endocytosis of mGluRs
56
Synaptic inhibition
reduces the probability of firing an action potential
57
A synaptic potential can be
depolarizing and yet be inhibitory.
58
Depolarizing synaptic
potentials can inhibit neurons as long as
ECl- is more hyperpolarized (negative)
than the action potential threshold (C).
59
GABAa or glycine receptors open chloride channels, which
results in inward flow of
negatively charged Cl- ions → hyperpolarization (B).
60
In developing neurons the intracellular Cl- concentration is controlled by
the Na+/K+/Cl- co-transporter, yielding high intracellular levels of Cl-→ ECl- is often more positive than AP threshold (always depolarizing).
61
In adult neurons the intracellular Cl- concentration is controlled
by
a K+/Cl- co-transporter pumps Cl- out of the cell, lowering
the internal Cl-, making ECl- much more negative → hyperpolarization.
62
Ionotropic GABA receptors (GABAa
and GABAc) consists of
* 5 subunits (heterodimeric)
* Integral chloride (Cl-
) channel
63
Ionotropic GABA receptors (GABAa
and GABAc) are found at
20%-50% of all
synapses in the brain
64
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
65
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
66
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
67
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
68
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
69
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
70
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
71
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
72
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
73
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
74
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
75
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
76
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
77
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
78
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
79
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
80
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
81
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
81
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
82
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
83
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
84
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
85
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
86
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
87
Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
88
Function of Metabotropic GABA receptors (GABAb)
* stimulate opening of K+ channels.
* *Opening of K+ channels inhibits/hyperpolarizes
the cell by bringing the membrane potential closer to EK+
`
* inhibit Ca2+ channels (mostly presynaptic) → also leads to hyperpolarization, less NT release
89
Activation of presynaptic GABAB
autoreceptors can
inhibit release of
GABA from the terminal.
90
# Presynaptic actions of GABAB
receptors
Under some conditions spillover can also occur onto
neighboring excitatory
synapses. There, GABAB
activation inhibits release of glutamate (left).
91
presynaptic GABAb
receptors also inhibit
release of dopamine,
norepinephrine and serotonin
92
Three types of Catecholamines
Dopamine
Noradrenaline
Adrenaline
93
In the CNS, catecholamines act as
neuromodulators, influencing
the effects of other, classical neurotransmitters.
do not evoke EPSP or IPSP by themselves,
rather make EPSP / IPSP larger or smaller
→ alter ion channels to modulate cell’s excitability, so that when
synaptic inputs arrive the neuron is either more ready to fire
action potentials or hyperpolarized / less excitable
94
Tyrosine hydroxylase
rate-limiting enzyme in synthesis of all
cathecholamines
Can be phosphorylated by at least 9 distinct
protein kinases (including PKA, CaMKII, PKC).
95
Tyrosine hydroxylase is upregulated by
* Stress
* caffeine
* nicotine
* morphine
induce increases
in catecholamine
synthesis
96
Tyrosine hydroxylase is downregulated by
antidepressants (chronic!)
