Neurotransmitters 2 Flashcards
The major inhibitory transmitter in CNS
GABA (gamma-aminobutyric acid)
As many as ___ of the synapses in brain use GABA, most common in ______
1/3, local circuit interneurons (talk to each other by electrical and chemical synapses)
GABA is derived from ____ and is/is not used in protein synthesis
Glucose metabolism, is not used in protein synthesis
Like Glutamate, levels of GABA are high/low
High (mM)
Glutamate is converted into GABA in one step via this enzyme
Glutamic acid decarboxylase (GAD)
GAD requires what for activity?
Pyridoxal phosphate (VB6 active form)
How can VB6 deficiency cause seizures?
Vitamin B6 needed for GAD activity, need GAD to make GABA neurotransmitter
When GABA action is terminated, it has these two fates using which transporter?
- Uptake into presynaptic terminal to be reused
- Uptake by glial cell where GABA is metabolized/degraded (different than w. uptake of glutamate, which gets converted to glutamine and then reused by presynaptic cell)
Both use GAT (GABA transporter)- family of 4 GATs
GABA uses what transporter to get concentrated in SVs
VIATT
Unlike Glutamate, GABA has this one major job
Intercellular signaling
During development, GABA is excitatory/inhibitory
excitatory
During development, intracellular Cl- is (higher/lower), and reversal potential for Cl- is (above/below) threshold. GABA is inhibitory/excitatory, and opens ion channels, causing (hyper/depolarization)
intracellular is higher (35 mM)
reversal potential is above threshold (-30 mV)
GABA is excitatory
Ion channel opens, Cl- leaves cell, causing depolarization
triggers Ca2+ influx and signaling
In adult, intracellular Cl- is (higher/lower), reverse potential for Cl- is (above/below) threshold, GABA is inhibitory/excitatory and opens ion channels, causing (hyper/depolarization)
Intracellular Cl- is lower (5mM) reverse potential is below threshold (-70) GABA is inhibitory Opens ion channels and Cl- enter cells Causes hyperpolarization
GABA is synthesized by these two GAD genes
GAD67, GAD65
This GAD gene is rate limiting; influences cellular GABA content in dosage-dependent manner; turns over rapidly
GAD67
Major inhibitory transmitter in the spinal cord
Glycine
Glycine is made from ___ by mitochondrial isoform of this enzyme
Serine; Ser hydroxymethyltransferase (Ser HMT)
Like GABA, Gly uses this transporter to get into SVs
VIATT
Fate of glycine after taken up by astrocyte
degradation
after release, Gly gets taken up by astrocytes or presynaptic vesicles by these two transporters
GlyT1 (astrocytes)
GlyT2 (pre-synaptic)
This makes either GlyT1 or GlyT2 lethal
KO
Three important catecholamines
Epi, Norepi, dopa (all from tyrosine)
Catecholamines are made by what percentage of neurons in brain
<1%
almost all neurons are close to a terminal releasing
catecholamines (small number of cell bodies, but lots of processes that go pretty much all over brain)
Main base for catecholamines
Substantia nigra and ventral tegmental area
Rate limiting step in catecholamine biosynthesis. What does it require?
Tyrosine –*–> Dihydroxyphenylalanine (DOPA)
*tyrosine hydroxylase
requires Fe and O2
Aromatic amino acid enzyme that is not rate limiting; non specific, fast, needs pyridoxal phosphate
DOPA —*—> Dopamine (dopamine neurons stop here)
*DOPA decarboxylase (also called aromatic amino acid decarboxylase, AAAD)
List steps for catecholamine biosynthesis starting from Dopamine. List the two enzymes. Where do sympathetic neurons mostly stop?
Dopamine —> Norepinephrine (dopamine beta-monooxygenase [ Sympathetic neurons stop here]
Norepinephrine —> Epinephrine (PNMT, uses S-adenosylmethioine to make it)
Where is Dopamine beta-monooxygenase located?
Inside vesicles (dopa -> norepi)
This transporter transports dopa, norepi, and epi uphill into vesicles as protons leave
VMATs (vesicular monoamine transporters)
Adrenal chromaffin cells and a few CNS neurons make this catecholamine
Epinephrine
Catecholamine storage
small dense core vesicles
In converting dopamine to norepi, dopamine beta-monooxygenase (dopa beta hydroxylase) has some interesting requirements. List the 3
O2, vitamin C, copper
Norepi influences these 4 behaviors
sleep, wakefulness, attention, feeding behavior
Which three enzymes in synthesis of catecholamines are cytosolic?
- TH (tyrosine hydoxylase)
- AAAD
- PMNT
This transporter is more neuroendocrine in all cells of adrenal medulla
VMAT1
This transporter is in peripheral, central, and enteric neurons
VMAT2
Explain why vesicular stores of catecholamines are dynamic
VMAT-mediated uptake is countered by leakage of catecholamines back into pre-synaptic cytosol
What is a key step in catecholamine signaling?
Reuptake; most of catechs released from a nerve terminal is retrieved; ends transmitter action and allows re-use
What does cocaine inhibit?
Dopamine transporter (DAT)
What upregulates DAT but not VMAT1 or 2?
Chronic cocaine
Synaptic vesicles that contain catecholamines can be small or large, and they are electron dense. List 5 important things they contain
- Chromagranin A (protein)
- D beta M (DBM)
- Bioactive peptides
- ATP
- Ascorbate
*catecholamine storage have many of the same proteins as ACh vesicles *
pH inside vesicle
5.5
Where does breakdown/metabolism of catecholamines occur?
Primarily in neuron that made it
In the process of removal, this enzyme oxidizes dopa, NE and epi, forming short-lived catecholaldeydes
Monoamine oxidase (MAO)
What makes supply of catecholamines available to MAO?
Vesicular uptake and leakage
Plasma membrane catecholamine transporters and vesicular catecholamine transporters are (related/unrelated)
unrelated
Histamine is made by neurons in this region of the brain
Hypothalamus (with projections to spinal cord and most brain regions)
mediates arousal and attention
histamine
Serotonin is used in groups of neurons in what areas of brain
Neurons in pons and upper brainstem with widespread projections to forebrain
What does serotonin affect?
Sleep and wakefulness
Serotonin is made from
tryptophan (dietary requirement)
How does Serotonin synthesis resemble that of catecholamines? List 5.
- Hydroxylase, rate limiting step
- AAAD
- molecular O2
- VMAT transport
- Cytosolic enzyme
Inhibitory local circuit neurons use what type of peptides?
Opiate peptides
This is a serotonin (5-HT) specific plasma membrane transporter, homologous to DAT and NET
SERT
Every gene encoding a neuropeptide encodes a prepropeptide with an ___-terminal signal sequence
NH2-terimnal
What guides ribosomes translating mRNA encoding pre-proneuropeptide to membranes of ER?
Signal sequences
You need this type of enzyme to release active peptides from inactive precuror: they recognize specific cleavage sites
Endoproteases
All of the pieces of the precursor are usually secrete (together/separately)
Together
Synthesis of neuropeptides occurs here
Nerve terminal
Is there re uptake of peptides?
No; once released, no-reuptake
Do many synapses use both small molecule and peptide transmitters?
YES!
Release of small molecule neurotransmitters in small clear core vesicles (SSVs) occur with (high/low) frequency stimulation (widespread/localized) increase in Ca2+
Low frequency stimulation, and localized increase in Ca2+
Release of peptides from large dense core vesicles (LDCVs) require what type of frequency stimulation and what type of increased in Ca2+?
Higher frequency stimulation, more widespread increase in Ca2+
major inhibitory transmitter in spinal cord
glycine
