1
Q
neurons communicate with one another by…..
A
releasing chemical messengers called neurotransmitters
2
Q
main excitatory neurotransmitter
A
glutamate
3
Q
main inhibitory neurotransmitter
A
GABA
4
Q
how to evoke synaptic response
A
binding to and activating neurotransmitter receptors, yielding any possible modes of synaptic signalling
5
Q
after activating neurotransmitter receptors, neurotransmitter are removed from synaptic cleft by…
A
neurotransmitter transporters or degradative enzymes
6
Q
3 different classes of neurotransmitters
A
1) classical (small molecule transmitters
- ACh, amino acids, biogenic amines derived from amino acids, purines
2) peptides
- endorphins etc.
3) non-classical, small molecule
- NO
7
Q
neuropeptides
- examples
A
- relatively large transmitter molecules (3-36 amino acids)
- endophrins, enkephalins, neuropeptide Y, vasoactive intestinal peptide, substance P, FMRDamide
8
Q
small molecule transmitter
A
- individual amino acids (ex: glutamate, GABA)
and transmitters (ACh, serotonin, histamine) - smaller than neuropeptides
- divided into: acetycholine, amino acids, purines, biogenic amines
9
Q
what are biogenic amines
- examples
- subgroup
A
- small molecule transmitter (subgroup)
- similar chemical properties and postsynaptic actions
- examples: dopamine, norepinephrine, epinephrine, serotonin, histamine
- catcholamines (subgroup)
10
Q
what are catcholamines?
A
- biogenic amine subgroup
- hydroxylated benzene ring
11
Q
Acetylcholine
- basic processes to all chemical synapses (4)
- where is it made?
A
- synthesis
- package and release
- reception
- removal (simple slow diffusion)
- made in cytoplasm
12
Q
synthesis of ACh
- precursors (2)
- enzyme
- transporter
A
- synthesized in nerve terminals, from precursors acetyl coenzyme A (kreb cycle) and choline
- enzyme: reaction catalyzed by choline acetyl transferase (ChAT or CAT)
- transporter: after synthesis in cytoplasm, vesicular ACh transporter loads ~10 000 molecules of ACh into cholinergic vesicle
13
Q
how to determine the evolution of ACh?
how do we know which tranmitter is used by which neuron for which function?
A
- raise antibodies against ChAT (enzyme)
- knockout genes (synthesis of ChAT)
- any mutation of the enzyme is quickly lethal mutation
14
Q
locations of ACh in vertebrate nervous system
A
- all motor neurons= spinal cord and brainstem
- autonomic nervous system (sympathetic and parasympathetic divisions)- fight or flight
- modulatory neurons in brainstem and basal forebrain- often involved with levels of activation (sleep/wake)- susceptible to Alzheimer’s (boost ACh to relieve some symptoms)
- intrinsic neurons= basal ganglia, tectum
15
Q
reception of ACh- 2 major types of receptors
A
1) nicotinic receptors
2) muscarinic receptors
16
Q
nicotinic receptors
- example found..?
- iono/metabo
- conduct?
- made up of.. ?
A
- important for reception of ACh
- ex: found neuromuscular junction
- ionotropic
- conduct both Na and K (depolarizing- net flow of Na override outflow of K)
- composed of 5 subunits with 3-4 transmembrane domains which form a channel with central membrane-spanning pore
- ligand-gated channel - binding ACh, causes conformational change, rearranges receptor domains, opening gate, permittion ions to diffuse through pore
17
Q
where does ACh bind on nicotinic ACh receptors?
A
on the alpha-subunit
usually has 2 alpha subunits at neuromuscular junction
18
Q
muscarinic receptors
- example, found where?
- iono/metabo
- when do you want to use these?
- structure
A
- ex: targets of parasympathetic postganglionic neurones
- found on receptors of parasympathetic nervous system, heart muscles
- metabotropic receptor
- use ACh to speed up/slow down processes (ex: beating of heart)
structure:
- 7 transmembrane domains
- extracellular site to bind neurotransmitter
- intracellular site to bind G-protein
- activate inward rectifier K channels or Ca-activated-K channels, exerting inhibitory influence on dopamine-mediated motor effects
19
Q
subtypes of muscarinic receptors
how does ACh bind?
A
M1, M2, M3, M4, M5
- different binding characteristics
- different reactions to drugs
- no subunits, each protein forms a complete receptor with its transmembrane domains
20
Q
G-protein receptors
- iono/metabo
- how does it work
- 2 examples
A
- metabotopic receptor
- work indirectly to regulate activity in numerous other proteins including channels
- receptor lies within membrane, can mind to transmitter, has intercellular domain that can react to G-protein
- heterotrimeric or monomeric
21
Q
2 differences between ionotropic and metabotropic receptors
A
1) speed (fast vs long lasting effects)
- fast= ionotropic
- slow= metabotropic
2) multiple actions
22
Q
how any subtypes of muscrinic receptors are there?
A
5
23
Q
removal of ACh
A
- post synaptic actions of ACh at many cholinergic synapses, is terminated by hydrolytic enzyme= acetylcholinesterase
- enzyme is concentrated in synaptic cleft, ensuring rapid decrease in ACh concentration after its release from presynaptic terminal
- choline produced by ACh hydrolysis, is RECYCLED by being transported back into nerve terminals, where it is used to re-synthesize ACh
24
Q
Why is the process of chemical synapses of ACh important?
A
- differential effects of toxins and drugs– pharmacology
- Agonists (drug mimics specific transmitter)
- antagonists (blocks transmitter)
- disease affecting cholinergic transmission
25
what is agonist and antagonist
- agonist= mimic endogenous ligand
antagonist= block endogenous ligand
26
example of nicotinic agonist
cholinergic substance
| nicotine
- nicotine binds to nicotinic receptors
27
nicotinic antagonist
- a-bungarotoxin from krait (used by snake, paralyze prey), prevents ACh from opening postsynaptic ion channels
- A-neurotoxin from cobra (blocks nicotinic receptor)
- curare (used as poison on darts to kill animals, blocks nicotinic receptors)
28
3 examples of muscarinic agonist and antagonist
- muscarine from the Amarita mushroom
- Summer flower
- Atropine from deadly nightshade (autumn berry)
29
effects of myasthenia gravis on neurotransmission and basis of treatment
- myasthenia gravis= disease that interferes with transmission between motor neurons and skeletal muscle fibers
- effects: autoimmune destruction of nicotinic receptors
- immunse responses reduced number of functional receptors at neuromuscular junction, eventualyl destroys them, diminishing efficiency of synaptic transmission
- muscle weakness occurs b/c motor neurons are less capable of exciting the postsynaptic muscle cells
- inhibitors increase concentration of ACh at synaptic cleft, allowing more effective activation of postsynaptic receptors not yet destroyed by immune system
30
each transmitter must always have mechanism for (4)
- synthesis
- package and release
- reception
- removal
31
Glutamatergic synapse
- synthesis
- packaging
glutamate= non essential amino acid, does not cross blood-brain barrier, therefore must be synthesized in neurons from local precursors
- every cell in body has glutamate
Synthesis
- glutamate can be synthesized from glutamine
packaging
- into synaptic vesicles by variety of vesicular glutamate transporters (VGLUT)
32
locations of glutamate in vertebrate nervous system
- most common fast transporter in the brain
- many primary sensory cells (ex: photoreceptors, olfactory receptors)
- many higher order/relay sensory cells (ex: retinal ganglion cells)
- many cells in cortex, and sub-cortical nuclei (ex: basal ganglia)
33
2 classes of glutamate receptors
1) ionotropic
| 2) metabotropic
34
structure of metabotropic glutamate (mGlu) receptors
- similar to muscarinic receptors
- 7 transmembrane domains
- extracellular site to bind neurotransmitter
- intracellular site to bind G-protein
- metabotropic= slow
- many classes
- glutamate can mediate excitatory vs inhibitory actions into postsynaptic cells depending upon receptor type
35
structure of ionotropic glutamate receptors
- similar to nicotinic receptor
- 3-4 common transmembrane domains
- with only 4 sub-units per channel
36
3 subgroups of ionotropic glutamate receptors
1) AMPA
2) Kainate
3) NMDA (aka non-NMDA)
these receptors are
- glutamate- gated cation channels that allow passage of Na and K (similar to nicotinic)
- always produce excitatory post synaptic responses
37
Non-NMDA receptors
(ionotropic glutamate receptors)
- generally non-selective for monovalent cations (both Na and K)
- excitatory
- generally fast opening and closing
38
gating NMDA receptor
- Ca in addition to K and Na
- glycine has to be binding to NMDA receptor
- Mg tends to block so nothing can cross (at hyperpolarized membrane potentials), inside the pore, have to depolarize the postsynaptic membrane to push Mg out
- NMDA receptors pass cations only when postsynaptic membrane potential is depolarized (during activating of strong excitatory inputs or during AP firing in postsyanptic cell)
39
if want Ca into cell that responds to glutamate, what should you do?
- have NMDA receptor present in cell (b/c permeable to K, Na and Ca)
40
NMDA receptor could act as "coincidence detector" how??
- parallel with classical conditioning
- -- need 2 stimuli, release glutamate and other pathway allowing depolarization
- implications for understanding how we learn
(block NMDA receptor, often block learning)
41
glutamatergic synapse
| - removal
- reuptake using excitatory amino acids transports (EATTs)
- uptake by glial cell
- -- conversion to glutamine (via enzyme glutamine synthetase)
- -- uptake by presynaptic terminal
- -- reconversion to glutamate
42
insufficient removal of glutamate in extracellular space causes...
(what happens during ischemia (stroke))
- excess depolarization
- leads to more glutamate release
- leads to more depolarization
- leads to more glutamate release
(vicious circle of EXCITOTOXICITY)
- runaway depolarization
- massive Ca influx
- mechanisms unclear but may involve activation of caspases leading to cell death
43
GABAergic synapse
- synthesis and packaging
- removal
synthesis
- from glutamate
- glutamic acid decarboxylase (glutamate with 1 carboxyl group chopped off)
packaging
- get into vesicles by vesicular inhibitory amino acid transporter (VIATT)
removal
- GABA transporter (GAT)
44
where are GABAergic synapses?
- GABA= most abundant inhibitory transmitter (fast)
- found throughout the brain
- mostly local circuit neurons but also projection neurons (Purkinje cells of cerebellum)
45
GABA receptors (3)
GABAb= metabotropic
- generally increase K currents
- tend to hyperpolarize cells
- inhibitory
GABAa and GABAc= ionotropic
- composed of multiple subunits
- Cl is main permeanant ion
- activation of the receptors cause influx of negatively charged Cl that inhibits the postsynaptic cells
46
ionotropic GABA receptors
- mediate inhibition through increase Cl permeability (hyperpolarize cell)
- multiple binding sites for GABA and variety of antagonists and modulators
(benzodiazepine, barbituates, steroids, picrotoxin)
47
4 types of agonist/antagonist ionotropic GABA receptor
1) Benzodiazepine
- agonist
- increase inhibition, decrease activity in brain
2) barbituates
- agonist
- binding sites are located within pore of domain
3) steroids
- interact with some extracellular receptors
- binding sites are located within pore of domain
4) Picrotoxin
- antagonist
- binding sites are located within pore of domain
48
glycine is ____ transmitter found in the ___ ___
inhibitory transmitter
in the spinal cord
49
Glycinergic synapse
- synthesis
- packaging
- reception
- synthesized from serine
- uses VIATT (vesicular inhibitory amino acid transporter) to package into vesicles (loads GABA into vesicles)
- used glycine transporter for uptake to terminals and glia
- receptors are ligand-gated Cl channels
(inhibition, hyperpolarizing)
- structure mirrors GABAa receptors
50
styrchnine
- glycine antagonist
- blocks inhibitory synapses in spinal cord
- over excitation of most muscles (including breathing)
- comes from tree in eastern asia
- rat poison
51
biogenic amines
| small molecule transmitters
- all are simple modifications from common amino acids
- catecholamines derive from tyrosine
- indolamines derive from tryptophan
- imidazolamines drive from histadine
52
5 biogenic amine neurotransmitters
3 are catacholamines- derived from tyrosine
1) dopamine
2) norepinephrine
3) epinephrine
4) histamine
5) serotonin
53
synthesis of catacholamines (5)
1) tyrosine
- tyrosine hydroxylase (add hydroxyl group)
2) L-DOPA
- DOPA decarboxylase
3) Dopamine
- Dopamine Beta Hydroxylase
- reward pathway
4) norepinephrine
- PRMT
5) epinephrin
54
what is Parkinsons disease caused from
| - how to treat
- Parkinson's disease= death of dopamine containing cells
| - treat by adding L-DOPA, will provide enough dopamine cells to run system
55
where does dopamine originate from?
| - where is it found
originated in substantia nigra and VTA
- found in projections throughout brain
56
dopaminergic synapse
- synthesis
- packaging
- removal
- metabotropic receptors
- synthesized by tyrosine
- packaging using vesicular monoamine transporter (VMAT)
removal
- reuptake: high affinity, Na-dependent dopamine transporter (DAT
- catabolism of dopemine enzymes: monoamine oxidase (MAO) and catechol O-methyltransferase (COMT)
- once release, dopamine acts exculsively by activating G-protein coupled receptors
Metabotropic receptors
- D1-4, which work primarily through inhibitory and excitatory actions on adenylyl cyclase, thus regulating cAMP levels
- activating/inhibiting adenyly cyclase
57
importance of dopamine (4)
1) Parkinson's disease
- death of many monoaminergic (dopaminergic, adrenergic, serotonergic) cells, particularly cells of substantic nigra which project to striatum
- motor deficits
- treatment with L-DOPA
2) schizophrenia
- treatment with D2/D4 antagonists
- drugs working as antipsychotics
3) reward and addiction
- ex; self-stimulation pathwyas
4) drugs
- amphetamines facilitate the release and block re-uptake of dopamine (and other catacholamines)
- cocaine: block re-uptake mechanism
58
cocaine
- blocks dopamine re-uptake
- prolongs its action at synapse
- too much dopamien, have symptoms of cocaine
- cocaine reduce psychotropic effects by inhibiting DAT, increasing dopamine concentrations in synaptic cleft
59
where is norepinephrine originated?
- where is it found?
- influences?
- originated in locus coeruleus
- found in projections throughout brain and spinal cord
- also the transmitter used by the sympathetic ganglion cells to control peripheral targets
- influences sleep and wakefulness, attentiona and feeding behaviour
60
where does epinephrine originate?
| - where is it found?
- originates in medullary neurones
| - found in projections to brainstem (hypothalamus) and spinal cord
61
adrenergic/noradrenergic synapse
| - what does it do?
- epinephrine and norepinephrine, importnat in autonomic nervous system and hormonal system
- mediate responses to dangerous/stressful stimuli and account for increase heart rates, dilated airways, shunting of bloodflow from digestive system and into muscles (etc)
- also involved in other visceral functions like bladder control and sexual arousal
62
adrenergic/noradrenergic synapse
- synthesis
- packaging
- removal
- metabotropic receptors
- synthesis: from tyrosine to L-DOPA to dopamine
- packaging using same VMAT (vesicular monoamine transporter)
removal
- re-uptake: high affinity norepinephrine transporter (NET)
- monoamine oxidase (MAO)
- catechol O-methyltransferase (COMT)
metabotropic receptors
- a1, a2 (alpha)
- b1, b2, b3 (beta)
63
serotonergic synapse
- synthesis
- packaging
- removal
- multiple receptors
synthesis: from typtophan
packaging: with VMAT (vesicular monoamine transporter)
removal
- re-uptake: serotonin selective transporter (SERT)
- MAO (monoamine oxidase) - break down
multiple receptors
- ionotroic: 5-HT 3
- metabotropic: 5-HT 1,2,4,5,6,7
64
where is serotonin originated
| -where is it found
originates in raphe nuclei
- found in projections throughout brain and spinal cord
65
LSD
- serotonin agonist
| - overstimulation of serotonergic pathways
66
histaminergic synapse
- synthesis
- packaging
- removal
- metabotropic receptors
synthesis: from histadine
packaged: VMAT (vesicular monoamine transporters)
removal/degradation: by MAO and histamine methyltransferase
metabotropic receptors
- H1, H2, H3
67
where is histamine found
role
- neurons in hypothalamus
- projections throughout nervous system
- plentiful in mast cells involved with inflammatory processes throughout the body
role
- projections mediate arousal and attention
- allergic reactions or tissue damage cause release of histamine from mast cells in bloodstream
68
roles of monoamines in affective disorders
- monoamine oxidase inhibitors (MAO-I) are effective anti-depressants
- tricyclic anti-depressants inhibit re-uptake transporters for all monoamines
- serotonin selective re-uptake inhibitors (SSRIs) are among most precribed medications
69
purines as transmitters
| - 2 examples
- ATP
- Adenosine
- often packaged together with other more conventional transmitters
70
2 types of purine receptors
metabotropic and ionotropic receptors
- broad classes of both
```
metabotropic= A and P2Y receptors
ionotropic= P2X receptors
```
71
effects of caffeine
- purine antagonist
| - disrupt the adenosine pathways in brain
72
5 broad classes of neuropeptides in vertebrates
1) brain-gut peptides
2) opioid peptides
3) pituitary peptides
4) hypothalamic-releasing peptides
5) miscellaneous peptides
73
opioids tend to be ___
- come from
- example of drug that binds
- tend to antidepressants
- come from the poppy
- heroin has specific receptors in cells bind to opium (?)
74
3 endogenous substances that bind to the same proteins as opium derivatives
1) endorphins
- mimic actions of morphine
2) enkephalins
3) dynorphines
75
synthesis of peptides from larger precursor protein
- often multiple copies of small peptides on precursor
| - need large amounts because they are secreted
76
where are peptides synthesized and packaged?
- are they able to be recycled?
- ER and Golgi located in the soma
| - metabolically expensive, cannot recycle
77
peptidergic transmission depends directly upon..
axonal transport to supply transmitter to synapse
78
peptidergic synapse
- synthesis
- packaging
- removal
- receptors
synthesis: from amino acids
packaging: in Golgi apparatus, plus axonal transport
removal: by diffusion, relatively no selective extracellular peptidases (no recycling)
receptors
- metabotropic and often varied for each peptide
- µ, (delta), K receptors for opiates
- often release with other transmitters
79
non-covential transmitters
- involved with..
- release
- involved with intercellular signalling
- release regulated by Ca
- non-vesicular release (not stores in SV)
- not confined by cellular membrnaes
- often associated with retrograde signalling (post--> presynaptic cells)
80
endocannabinoids
- derived from
- action
- depolarization effects
- derived form fatty acids
- endogenous signals that interact with cannabinoid receptors
- anandamide
- 2-AG
action: inhibition of communication between postsynaptic cells and their presynaptic input
depolarization of postsynaptic neuron causes transient reduction in inhibitory postsynaptic transmission
- depolarization reduces synaptic transmission by elevating [Ca] within postsynaptic neuron
- rise in Ca triggers synthsis and release of endocannabinoids from post synaptic cell
81
nitric oxide (NO)
- synthesis
- specializations at synapses (transmission)
- direction of pathways
- endogenous structure
- gaseous neurotransmitter
- synthesis in presynaptic cell, release regulated by Ca
- no normal membrane specializations at synapses, the presynaptic cell could be a postsynaptic cell (retrograde transmission)
- pathway is not always in one direction
82
other possible non-covential transmitters (2)
CO and H2S
| - also some other gaseous neurotransmitters
83
are transmitters same across animal kingdom?
- some animals use them differently
| ex: insects, visual system uses histamine (as opposed to glutamate in vertebrates)
84
diversity of transmitters in invertebrates
- many molluscs have only 10s of thousands of neurones (as opposed to 10s of billions of neurones in our brains)
- molluscs contain many neurotransmitters as vertebrates
85
molluscan neurotransmitters (8)
1) serotonin
2) histamine
3) catecholamines (dopamine, norepinephrine)
4) Acetylcholine
5) glutamate
6) GABA
7) Nitric oxide
8) numerous peptides (some same as vertebrates, some different - FMRFamide)
NESC 2570
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