Which techniques can we use to monitor the action of neurotransmitters?
microdialysis
extracellular levels
(Konz. von Substanzen, Messung über Diffusion)
patch clamp
ion channel activity
immunhistochemistry
localization
genetic models
function
Which structures can you see?
How is the activation process?
AP arrives
electrical —> chemical signal conversion
voltage-gated calcium channels get open
synaptic vesicles fuse with presynaptic membrane (fusion process via SNARE protein) = Priming
presynaptic release of neurotransmitter triggered bei Ca
diffusion across synaptic cleft
postsynaptic receptor binding and activation
How is the activation process terminated?
Reuptake transporters
Proteins (e.g. SERT for serotonin) pump the neurotransmitter back into the presynaptic neuron
Degrading enzymes
Enzymes (e.g. Acetylcholinesterase AChE) break down the neurotransmitter (e.g., ACh) in the cleft.
negative feedback
Receptors on the presynaptic neuron sense how much neurotransmitter has been released and inhibit further release
Wie ist die SNARE machinery aufgebaut?
Synaptobrevin = vesicle
builds SNARE complex with membrane proteins
Syntaxin + SNAP-25
partners of Synaptobrevin in presynaptic membrane
SNARE complex = Synaptobrevin + Syntaxin + SNAP-25
Zippering of the 3 proteins drive fusion
Synaptotagmin = Ca2+ sensor
triggers fusion through Ca2+ influx
What is the Co-existence principle?
neutrons typically contain two neurotransmitters
1 aa or amine (meist ionotrop)
1 peptide (=co-transmitter) (meist metabotrop)
—> synergistic or antagonistic
Which neurotransmitter classes do we distinguish?
Classical neurotransmitters (high concentration)
aa: gutamate, GABA
amines: dopamine, serotonine
ACh
Non-classical (low concentration, synthesis only in soma)
gases: NO
lipids: endocannabinoids
neuropeptides: endorphins, …
What determines whether a neurotransmitter is excitatory or inhibitory?
the receptor
Which neurotransmitters are classically excitatory or inhibitory?
Glutamate
excitatory
GABA
inhibitory
Glycine
What is the basic substance of Glutamate and GABA?
Glutamine
How is GABA synthesised?
enzymatic transition of Glutamate through Glutamic acid decarboxylase (GAD)
Which role play the astrocytes in Glutamate/GABA synthesis
= Neurotransmitter recycling
reabsorb the released GABA or glutamate from synaptic cleft
convert it into glutamine
—> make it available to the neurons once again for Glutamate/GABA synthesis
What function does ACh have?
main transmitter for
neuromotoral junctions
memory
attention
alertness
How is Acetylcholine synthesized? Which is the key enzyme?
Acetyl-CoA + Choline —> ACh
key enzyme: Choline-Acetyltransferase (ChAT)
How is ACh recycled?
enzymatic: ACh-Esterase (AChE)
Which 2 types of receptor classes do we distinguish?
ionotropic
neurotransmitter bind to ligand-gated ion channels
metabotropic (G-Protein coupled)
neurotransmitter bind to G-protein
What is the difference between ionotropic and metabotropic receptors?
metabotropic
via ion channels
via G-proteins,
no channels!
fast
slower
ion currents
second messengers (cAMP, IP3, DAG)
channel opens directly
—> ions flow across synaptic cleft
—> direct change in postsynaptic potential
—> fast depolarization or inhibition
intracellular signaling pathways
—> triggers a cascade involving second messenger
—> cellular effects like the opening of an ion channel
e.g. Glutamata, GABA-A, P2X
e.g. mGluRs (metabotrope Glutamat-Rezeptoren), P2Y
How can we subdivise ionotropic receptor classes?
P2X receptors
= purinergic receptors
e.g. relevant for pain, ATP release
Trimer
2 TM domains
keine cys loop
Cys loop receptors
Pentamer,
4 TM domains
cys loop e.g. inbetween M3 and M4 (= loop consisting of 13 amino acids, stabilized by a disulfide bond)
Glutamate-gated channels
Glutamate receptors
e.g. NMDA receptor activation (Ca2+ influx)
Tetramer
3 TM domains
Glutamate System has 4 receptor classes. Which ones and why?
AMPA
fast depolarization
mainly
Na+ influx
NMDA
Voltage-gated Mg²⁺ channel
Ca2+ influx
Kainate
modulatory
Metabotropic receptors
G-protein coupled receptors
GABA receptors: which ones?
= main inhibitory CNS neurotransmitter
GABA-A (e.g. image)
Cl-
ionotropic cys-loop receptor
GABA-B
GPCR
metabotropic receptor
What is special about the NMDA receptor activation?
orthosteric site = Glutamate, allosteric site = Glycine (acts as a Co-receptor)
—> Glutamine can´t bind when Mg2+ is blocked
acts as a “coincidence detector”
Glu = agonist
ketamine = antagonists
What are examples for Monoamines? Which substance is their precursor?
Dopamine
reward (Belohnung)
movement
Tyrosine
Serotonin
mood
sleep
Tryptophane
Adrenaline, Noradrenaline
arousal (Erregung)
What are examples for Metabotropic Receptors?
Gs
cAMP hoch
Gi
cAMP niedrig
Gq
IP3 + DAG —> Ca2+
What are second messengers?
second messengers transmit and amplify the signal within the cell
What is the mode of action of SSRIs and Ketamines?
= antidepressants
SSRI
block serotonin transporter
—> no resumption
—> serotonin stays longer in synaptic cleft
delayed therapeutic effects
Ketamins
NMDA receptor antagonist
—> Ca influx blocked
rapid
What is the difference between auto- and heteroreceptors?
= presynaptic receptors
autoreceptors: respond to the neurotransmitter released by the neuron itself in order to inhibit its further release
heteroreceptors: respond to neurotransmitters released by other neurons in order to modulate synaptic transmission
autoreceptors
feedback inhibition
e.g. GABA receptors
heteroreceptors
cross-modulation
e.g. GABA receptor at Glutamate Synapse
What are electrical synapses? What is the difference to chemical synapses?
chemical synapses: rely on neurotransmitters to transmit a signal
electrical synapses: based on the direct flow of ions through gap junctions
main difference = communication
CAVE: can´t change an excitatory signal into an inhibitory signal
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