Exam 2: Topic 5 P1 Flashcards
What 3 things define a neurotransmitter?
- location
- regulation
- function
what is the location of a neurotransmitter?
in synaptic vesicles at the axon terminal
what is the regulation of a neurotransmitter?
release is regulated by an action potential
- Minis are not an efficient means of communication for this ⇒ synchronized release
what is the function of a neurotransmitter?
once released it must bind and activate a postsynaptic receptor
- Ligand gated
- G-protein coupled
what does acetylcholine (ACh) do?
released by motor neurons at the neuromuscular junction and gives rise to mEPP’s as well as EPP when there is an AP ⇒ present in the CNS
which neurotransmitters are amino acids? (3)
- glutamate
- GABA
- glycine
what does glutamate do?
primary excitatory NT
what does GABA do? where is it mostly located?
inhibitory ⇒ NT and receptors are mostly in the brain
what does glycine do? where is it mostly located?
inhibitory ⇒ NT and receptors are mostly in the spinal cord
what are the major categories of biogenic amines? (3)
- Catecholamines
- Indoleamine
- Imidazole Amine
which NT’s are catecholamines? (3)
- dopamine
- norepinephrine
- epinephrine
which NT is an Indoleamine?
serotonin (5-HT)
which NT is an Imidazole Amine?
Histamine
which molecules are purines? (2)
- ATP
- adenosine
which neurotransmitters are neuropeptides? (2)
- 3-36 amino acids in length like methionine enkephalin
- endogenous opioids like endorphins
which NT’s are unconventional? (2)
- endocannabinoids
- nitric oxide
what are small molecule neurotransmitters?
anything that isn’t a neuropeptide or unconventional (basically everything else)
what are the 2 main categories of NTs?
small molecule neurotransmitters and neuropeptides
- unconventional is a smaller group
where are small molecule transporters not made in?
the cell body
- Enzymes are generated in the cell body transported on the axon
how do enzymes affect NT synthesis?
When enzymes are locally in the terminal it helps synthesize the NT
- Stored in small vesicles
where are peptide neurotransmitters processed?
in the rough ER or post translational modifications
how are peptide neurotransmitters made?
- Made from proteins ⇒ from genes
- A large protein is made in the rough endoplasmic reticulum (RER) and then undergoes proteolysis and sometimes other post-translational modification
- Protein travels through the RER and golgi and is put into large dense core vesicles
where does proteolytic processing happen for peptide neurotransmitters? (2)
both golgi and dense core vesicle
T/F peptide neurotransmitters are generated in the cell body and reduced in size
True
T/F peptide neurotransmitters are packaged and transported down the axon
True
T/F peptide neurotransmitters are not modified during transport?
False
- Modified during transport
where are peptide neurotransmitters stored?
dense core vesicles
cotransmitters
multiple types of NT in the same vesicles
- the presynaptic cell must release a vesicle in response to a stimulus
T/F you can preferentially/differentially release one type of synaptic vesicle depending on the input signal coming into the cell?
True
how does low frequency stimulate affect release of small molecule NTs?
it activates calcium gated channels but only some comes in due to the low frequency ⇒ or opening infrequently (grey cloud area)
- The calcium concentration doesn’t diffuse as far in the presynaptic cell
- It binds to synaptotagmin at the local vesicles causing them to fuse and release NT
what effect does low frequency have on small and large vesicles?
Small effect on the large dense core vesicles but large effect on clear core vesicles
- leads to release of small molecule NTs
how does high frequency stimulate affect release of small molecule NTs?
More calcium in and a larger response from the vesicles in the terminal
- This responds differently than before because they release clear core and the dense vesicles
how does low or high stimulate affect postsynaptic response?
this modulates the output of the presynaptic cell to affect the post synaptic response
T/F there is no pathway to generate the gas nitric oxide
False
- there is a pathway via arginine and NO synthase
what activity does NO affect?
presynaptic cell guanylyl cyclase to turn GTP to cGMPaffecting protein kinases
- Also passes through the plasma membrane of the cell into the synaptic cleft and then pass into neighboring cells ⇒ not necessarily those in the synapse
Ionotropic
ligand gated receptors ⇒ once the ligand is bound at the sites it opens the chanel and ions can go through
Metabotropic
-protein coupled receptor ⇒ doesn’t directly open or close channels but indirectly opens/closes channels by releasing the alpha subunit which binds to other proteins
where does the ligand bind on the G protein coupled receptor?
the extracellular area
what does the GPCR protein interact with?
with the G protein (alpha, beta, gamma) structure at the bottom
- Part of the G protein dissociates
what does the G protein do when it dissociates? (2 possible)
- Directly open or close the channel to allow ions through
- Uses an effector protein (cyclases) which also effect channels
what is the difference in speed between ionotropic and metabotropic?
- Ionotropic are fast and short term ⇒ on or off depending on binding
- Metabotropic are slower and long term ⇒ biochemical cascade leads to amplification of the signal (effect on the effector protein)
what types of subunits do ligand gated ionotropic receptors have?
hetero-tetramers or pentamers
T/F there are no ionotrophic channel receptors for dopamine, epinephrine, norepinephrine, histamine?
True
what are the 8 categories of ligand gated receptors?
- nACh
- AMPA
- NMDA
- Kainate
- GABA
- Glycine
- Serotonin
- Purines
what types of molecules do purine ligand gated receptors respond to?
Adenosine and ATP
why makes the general structures of ligand gated receptors? (4)
- ligand binding domain
- amino terminal domin
- transmembrane domain
- carboxyterminal domain
ligand binding domain
attached to the transmembrane domain and amino terminal domain on the other side where ligand binds to the receptor on the extracellular side
amino terminal domain
the most extracellular side where it helps guide and put the receptor in the plasma membrane itself
transmembrane domain
alpha helices to anchor the protein
carboxyterminal domain
region where if you want to modulate activity you can do it here intracellularly
what are the categories of metabotropic G protein coupled receptors? (8)
- muscarinic
- glutamate
- GABA-B
- dopamine
- adrenergic
- histamine
- serotonin
- purines
how many sub-parts do pentamers have? hetero-tetramers?
5; 4
what is the general architecture of GPCRs? (3)
- monomeric G protein extracellular side where the ligand binds
- monomeric G protein transmembrane units
- cytoplasmic G-protein side where the G protein binding site is
how many transmembrane regions do GPCRs have?
7
in what ways do GPCRs function? (3)
- Monomers ⇒ mAChR, D1R
- Homodimers ⇒ mGluR
- Heterodimers ⇒ GABA-B
Trimeric G protein
3 subunits that interact
- These are NOT part of the receptor
- The receptor needs to work through this structure
T/F the trimeric G protein is encoded by the same genes as the GPCR?
False
- They are encoded by separate genes
what is the generic life cycle of a NT? (6)
- Synthesis ⇒ somehow the neurotransmitter is synthesized
- Packaged into SV with a transporter
- SV releases
- Diffuses through the synaptic cleft
- NT receptor binding
- NT comes off the receptor
what 2 things can happen when the NT comes off the receptor?
- Degraded: the transmitter is enzymatically degraded
- Re-uptake: taken back up by glial cells or by the neuron that released it
what synthesizes acetylcholine?
glucose is converted to acetyl coenzyme A combined with choline through choline acetyltransferase (ChAT) enzyme
what packages acetylcholine?
vesicular acetylcholine transporter (VAChT)
- then released
what degrades acetylcholine?
acetylcholinesterase (AChE) enzyme in the synaptic cleft which degrades it back to acetate and choline
what is responsible for reuptake of acetylcholine?
choline transporter (ChT) ⇒ second source used to generate choline
what are the receptors for acetylcholine?
nACh
what do nACh channels let pass through?
Na+ and K+ ions
how many subunits do nACh have?
Heteropentamer ⇒ 5 subunits but have to have 2 alpha units
how many acetylcholine molecules must bind to an nACh receptor?
2
agonists for acetylcholine
acetylcholine endogenous, nicotine
antagonists for acetylcholine
mecamylamine binds to the receptor but blocks the receptor
agonists
chemical that activates a receptor to produce a biological response
antagonists
molecule that binds to a target and prevents other molecules (e.g., agonists) from binding
myasthenia gravis
muscle weakness, nystagmus (uncontrolled movement of the eye) and drooping eyelid
- Reduced amplitude of muscle APs
- Reduced number of mEPPs
- Autoimmune reaction reduces number of nAChR’s
what can you treat myasthenia graves with?
acetylcholinesterase inhibitors ⇒ neostigmine (degrades acetylcholine)
what is different when you stimulate motor neuron axons for non myasthenia gravis patients?
you get end plate potentials that are the same amplitude and follow the stimulation
- If you do this for someone who has this disease, there is a reduction in the amplitude of the action potential which gets weaker as stimulation increase
what is the biological problem with myasthenia gravis?
there is a problem with signaling but doesn’t suggest there is a problem with the NT release
- If you block the degradation you strengthen the muscle response => there is more in the synaptic cleft for a longer time which recovers the function
- Due to an autoimmune disorder where antibodies bind to the postsynaptic nicotinic receptor, block it from functioning, and destroy the receptors
- Fewer functional receptors which leaves a weaker response from an AP in the neuromotor axon
Muscarinic acetylcholine receptors (mAChR) agonists and antagonists
- Agonists: acetylcholine (endogenous), muscarine (mushroom toxin)
- Antagonists: atropine, scopolamin
what does the vagus nerve release and what does it bind to?
releases ACh and binds to M2 AChR on the heart
- when vagus is stimulated, there is a reduction in amplitude and contraction of the heart
- This is G-protein coupled receptor because there is a long term modulation change in the postsynaptic cells
what is the glutamate synthesis process?
glutamine is synthesized to glutamate by glutaminase enzyme
what is the packaging for glutamate?
vesicular glutamate transport (VGluT)
how does glutamate reuptake work?
- directly by Excitatory amino acid transporter (EAAT)
- indirectly to glia by glutamine synthetase
how is glutamate transported out of glia?
system N transporter 1 (SN1)
how is glutamate transported into the neuron?
System A transporter 2 (SAT2)
T/F glutamate transporter can be metabotropic or ionotropic?
True
is glutamate degraded?
Glutamate is not degraded just recycled
what are the 3 glutamate receptors?
ionotropic non selective channels
- AMPA
- Kainate
- NMDA
what ions do ligand gated glutamate receptors let in?
Na+, K+, maybe Ca2+
AMPA
GluA receptor subunits
- Ca2+ permeability depends on subunits
Kainate
GluK and sometimes GluA subunits
NMDA
GluN receptor subunits
- Permeable to Na+ and Ca2+
- Binds Mg2+ at hyperpolarized potentials which blocks until depolarization
what does NMDA require?
co-agonists Glycine or D-serine
what is different about NMDA AP graphs??
Longer and slower than AMPA and Kainate
- Only function when several properties of the cell happen at the same time
what are the kinetics like for each glutamate receptor?
- AMPA current is larger and kinetics are faster ⇒ open, ions flow fast and closes quickly (highest peak)
- NMDA stays open longer so there is more current over a longer time course (higher than kainate but lower than AMPA)
- Kainate is quick to open like AMPA and peaks at a lower current and doesn’t close quite as quickly (more like an NMDA receptor)
how many subunits does AMPA have?
heterotetramer so 4
what is the structure of the AMPA receptor? (4)
3 domains on each of the subunits (LBD, transmembrane, ATD) => when glutamate binds then the channel opens ⇒ when not bound then ions don’t go through
- Ligand binding domain
- Cytoplasmic and extracellular domain
- Plasma membrane
- Amino terminal domain
when is AMPA permeable to Ca2+? (2)
- The GluA2R is converted to GluA2Q
- There is no GluA2 unit
what codons are needed for permeability in the AMPA receptor?
GluA2R unit is impermeable to calcium and arginine replaces the glutamine via RNA editing
what enzyme converts GluA2Q to GluA2R?
ADAR2 enzyme converts a codon for glutamine (Gln; Q) to arginine (Arg; R)
- R is impermeable while normal Q is permeable
what do most AMPA receptors in the brain have?
edited GluA2R restricting CA2+
what are the properties of the NMDA receptor? (5)
- GluN2 subunits bind glutamate
- GluN1-3 subunits bind glycinate/d-serine
- Permeable to Ca2+
- Binds Mg 2+ at hyperpolarized potentials
- Required glycine (SC) or D-serine (brain) co-agonist for efficient gating
how may subunits does NMDA have?
heterotetramer so 4
what ions go through the NMDA channel?
Sodium, potassium, and calcium comes through the channel
end card
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