Chemical Messengers and Excitotoxicity Flashcards
What kind of receptors are used for EAA? (general)
ionotropic and metabotropic receptors
What are the three types of ionotropic receptors?
NMDA, AMPA, and Kainate receptors
What is influxed when the NMDA channel is activated?
calcium
What modulatory sites are found on the NMDA receptor?
binding site for the EAA, binding site for glycine, magnesium binding site, and PCP binding site (also ketamine)
what must the NMDA receptor have bound to it in order to open?
the EAA and a glycine molecule
What is blocking the NMDA channel from allowing the influx of Ca2+?
Mg2+ molecule
when will the Mg2+ molecule move into the ECF?
when the neuron become depolarized
What happens when the EAA binds to the AMPA receptor?
it will open and there will be an influx of Na+ ions
What modulatory site is found on the AMPA receptors?
the EAA binding site as well as a benzodiazepine modulatory site
what is the effect of a benzodiazepine binding to an AMPA receptor?
it reduces the amount of sodium that enters into the cell
What is unique to the Kainate receptor?
a small amount of Ca2+ will follow the entry of Na+ into the cell once the receptor is activated
What specifically depolarizes the NMDA receptor?
when the non-NMDA receptor is activated, there is an influx of Na+ into the cell, which produces a typical epsp, which will depolarize the NMDA channel and cause the Mg2+ to leave the receptor
What are the main functions of the non-NMDA receptors?
primary sensory afferents and upper motor neurons
what are the main functions of the NMDA receptors?
they are critical in short and long term memory formation and synaptic plasticity
how many groups are the metabotropic receptors divided into?
3
The group I metabotropic receptors are coupled to what G protein?
Gq
Groups 2 and 3 metabotropic receptors are coupled to what G protein?
Gi
what happens when a Gq protein is activated?
it causes an increase in IP3 and DAG which ultimately causes Ca2+ to be released intracellularly
what happens when a Gi protein is activated?
there is going to be a decrease in cAMP
what is the main function of pre-synaptic metabotropic receptors for EAAs?
they control NT release
what is the main function of post-synaptic metabotropic receptors for EAAs?
learning, memory, and motor systems
How do you limit the action of the EAA?
glial cells around the pre- and post-synaptic neurons have transporter proteins on them that take up the EAA
What does the transporter protein on the glial cell require?
the Na/K ATPase–> it is Na dependent
inside the glial cell, what happens to the EAA?
it is converted into glutamine
what happens to the glutamine once it is converted in the glial cell?
it is moved out of the glial cell and into the pre-synaptic cell
what happens to the glutamine once inside the pre-synaptic neuron?
it is going to be converted back into an EAA and then repackaged into the vesicle
What does calcium bind to once it flows inside the neuron?
calcineurin
what happens when calcium binds to calcineurin?
it is going to activate NOS
What does the NOS do?
it takes the AA arginine and cleaves off a nitric oxide (NO), giving us NO and citruline
What are the neural functions of NO?
effects on memory, cardiovascular and respiratory control
what are the non-neural functions of NO?
immunological effects and EDRF (endothelial derived relaxing factor)–> causes relaaxation of smooth muscle–> vasodilation
What are the harms of NO?
very unstable, leads to the production of free radicals, in high concentrations it is toxic to neurons
What are the 5 monoamines?
epinephrine, norepinephrine, dopamine, serotonin, and histamine
Where do you find the norepinephrine neurons?
locus ceruleus and other pontine/ medullary areas
where is the locus ceruleus found?
down in the brainstem
what is the role of norepinephrine?
wakefulness/ alertness
where do you find epinephrine neurons?
medulla
what is the role of epinephrine?
modulatory role
From which amino acid is dopamine, norepinephrine, and epinephrine derived?
tyrosine
what enzyme converts tyrosine into L-DOPA?
tyrosine hydroxylase
what happens once tyrosine is converted into L-DOPA?
it is then moved into vesicles and the norepinephrine is created if there is an enzyme for that inside the vesicle
what is the enzyme that converts norepinephrine into epinephrine?
PNMT
where does the conversion of norepinephrine into epinephrine occur?
outside the vesicle and then the epinephrine is moved back inside the vesicle
How is the norepinephrine/ epinephrine moved into the vesicles?
by the VMATs 1 and 2
what drug inhibits the VMATs?
reserpine
how is the action of norepinephrine, epinephrine, and dopamine limited?
reuptake and enzymatic degradation by MAO and COMT
what are the receptors for norepinephrine and epinephrine?
alpha and beta adrenergic
where do you find dopamanergic neurons?
in the basal ganglia, in the hypothalamus and limbic system, and in the cortex
what is the function of the dopamanergic neurons found in the basal ganglia?
motor control
what is the function of the dopamanergic neurons found in the hypothalamus and the limbic system?
they are involved in endocrine and emotional control
what are the receptors for dopamine?
there are 5 metabotropic receptors
what are the D1 and D5 receptors bound to?
a Gs protein
what happens when a Gs protein is activated?
there is an increase in cAMP
what are the D2 receptors bound to?
a Gi protein
what happens when a Gi protein is activated?
there is a decrease in cAMP, which causes a potassium efflux, which causes hyperpolarization of the cell
what are the D3 and D4 receptors bound to?
a Gi protein
where are the serotengeric neurons found?
in the cerebellum, in the raphe nuclei, and in the hypothalamus and limbic system
what is the function of the serotenergic neurons found in the hypothalamus and limbic system?
mood
what is the function of the serotenergic neurons found in the cerebellum?
modification of motor activity
what is the function of the serotenergic neurons found in the Raphe nuclei?
modification of motor and sensory activity
what amino acid is serotonin derived from?
tryptophan
what converts tryptophan into serotonin?
tryptophan hydroxylase
how do you limit the actions of serotonin?
reuptake and catabolism by MAO and COMT
what are the receptors for serotonin?
there are 7 with multiple subtypes, most of them are metabotropic but there is one ionotropic receptor
what happens when the 5HT3 receptors are activated?
vomiting
what happens when the 5HT6 receptors are activated?
there is an anti-depressant effect
where do you find histamine neurons?
tuberomammillary nucleus of the hypothalamus
what is the role of histamine in the tuberomammillary nucleus of the hypothalamus?
wakefulness
what amino acid is histamine derived from?
histidine
what enzyme is used to convert histidine into histamine?
histidine decarboxylase
how do you limit the actions of histamine?
reuptake and catabolism of diamine oxidase (DAO) and COMT
what are the receptors for histamine?
H1, H2, and H3
what type of receptors are the histamine receptors?
metabotropic receptors
which receptor for histamine is involved in wakefulness?
H1
what are the two major inhibitory amino acids?
GABA and glycine
where is the most amount of GABA found?
widely distributed throughout higher levels of the CNS
GABA is critical in what functions?
consciousness, motor control, and vision (retina)
what is GABA synthesized from?
glutamate
what is the enzyme that converts glutamate into GABA?
glutamate decarboxylase (GAD)
how is GABA transported into vesicles?
by vesicular GABA transporter protein
how is GABA removed from the synapse?
via GAT (two different forms)
where is GAT 1 found?
on the presynaptic terminal
where is GAT 2 found?
on glial cells surrounding the synapse
what happens if GAT1 takes up the GABA?
the GABA is repackaged into vesicles
what happens if GAT2 takes up the GABA?
the GABA is converted to glutamate then to glutamine and then released into the ECF where it will be taken up by the presynaptic terminal and recycled into GABA
What are the different types of GABA receptors?
GABA a and GABA b
what type of receptor is GABA a?
ionotropic (Cl-)
what happens when GABA a receptors are activated?
Cl- flows into the cell and the GABAa receptors produce ipsp in adult neurons
what are the other binding sites on the GABAa receptors?
benzodiazepine sites, ethanol sites, and certain steroids
what are the other binding sites on the GABAa receptors known to be?
potentiate, which means that they all increase the amount of Cl- that flows into the channel–> bigger ipsp–> cell is more inhibited
what was discovered to be special about the GABAa receptors?
it appears that there are large numbers of extra-synaptic GABAa receptors
what is the significance of extra-synaptic GABAa receptors?
they are believed to be the site of action for a number of general anesthetics, including propofol
what type of receptor is a GABAb receptor?
metabotropic
what is the GABAb receptor bound to?
a Gi/G0 protein
what happens when the Gi/G0 is activated?
a K+ channel is activated and a Ca2+ channel is inhibited
what is the role of GABAb receptors located pre-synaptically?
regulate NT release
what is the role of GABAb receptors located post-synaptically?
inhibition of post-synaptic cell
what is the function of glycine?
mediates many spinal inhibitions
what is glycine produced by?
unmodified amino acid
how do you remove glycine from the synapse?
GAT proteins and recycling
what type of receptor is the glycine receptor?
ionotropic (chloride)
what does an influx of chlorine lead to?
IPSP
what else can bind to a glycine receptor?
ethanol and general anesthetics (potentiate it) and strychnine (blocks it)
What are the purines?
ATP, ADP, and adenosine
what synthesizes ATP in the pre-synaptic terminal?
mitochondria
where are the regions where more purines are found?
cortex, cerebellum, basal ganglia, hippocampus
What are the receptors for adenosine?
P1
what is the function of post-synaptic adenosine receptors?
sleep induction and general inhibition of neural function
what is the function of pre-synaptic adenosine receptors?
inhibition of NT release
What type of receptor is the P2X receptor?
ionotropic
what is the ligand for the P2X receptor?
ATP
what type of receptor is the P2Y receptor?
metabotropic
what is the ligand for the P2Y receptor?
ATP, ADP, UTP, UDP
What is the P2Y receptor bound to?
a Gi/Gq protein
What is an example of a benzodiazepine?
valium (muscle relaxant)
What happens when histamine binds to the H1 receptor?
PLC activation
what happens when histamine binds to the H2 receptor?
increased CAMP (associated with gastric acid release)
what happens when histamine binds to the H3 receptor?
it is presynaptic, so it will cause a decrease in histamine release
the opioids are a family of peptides that include?
endorphins, enkephalins, dynorphins, and nociceptin
Where do you find the opioids?
basal ganglia, hypothalamus, and pontine and medullary sites
What are the general functions of the opioids?
modification of nociceptive inputs, mood/affect
what is the precursor of B-endorphins?
proopiomelanocortinin (POMC)
what is POMC the precursor to?
ACTH
what is the 4 AA chain precursor to the encephalins?
tyrosine-glysine-glysine-phenelalanine
what is the precursor for dynorphine?
pro-dynorphine (3 molecules of leu-enkephalin
what is the precursor for nociceptin?
orphanin FQ
how do you remove the opioids from the trough/cleft?
reuptake and enzymatic destruction
what are the two forms of enzymatic destruction for the opioids?
enkephalinase and aminopeptidiase
what type of receptors are the 3 receptors for the opioids?
metabotropic
what are the three receptors for the opioids?
mu-receptor, kappa-receptor, delta-receptor
what does activation of the mu-receptor cause?
analgesia, respiratory depression, euphoria, constipation, and sedation
what does activation of the kappa-receptor cause?
analgesia and dysphoria
what does activation of the delta-receptor cause?
analgesia only
what are all the metabotropic receptors for the opioids bound to?
Gi/G0 proteins
what happens to the Gi/G0 protein when the mu-receptor is activated?
it leads to an increase in potassium efflux and hyperpolarization
what happens to the Gi/G0 protein when the delta and kappa receptors are activated?
there is a decrease in calcium influx
what are the 2 identified endogenous endocannabinoids?
anadamide and 2-AG
where are the endocannabinoids found?
in the basal ganglia, spinal cord, and cortex
what is the function of the endocannabinoids in the basal ganglia?
mood and motor performance
what is the function of the endocannabinoids in the spinal cord?
modulation of nociception
what is the function of the endocannabinoids in the cortex?
neuroprotection
what are the endocannabinoids derived from?
membrane lipids (specifically arachidonic acid)
where does the endocannabinoid synthesis take place?
in the presynaptic terminal
what specific membrane lipid is the anandamide derived from?
NAPE
what specific membrane lipid is the 2AG derived from?
PIP2
What are the two receptors for the cannabinoids?
CB1 and CB2
what is activation of the CB1 associated with?
the psychoactive responses to the cannabinoids
where are the CB1 receptors located?
central nervous system neurons
where is the synaptic location of the cannabinoid receptors?
largely presynaptic
what is the effect of the CB1 receptors on EAA and GABA?
they reduce EAA and GABA release via a G1 coupled protein
where are CB2 receptors found in the brain?
on microglia
what would you suspect if there were CB2 receptors found on neurons (dendrites and within the soma)?
nerve injury
what does the CB2 have a higher affinity for?
2AG better than AEA
How can you degrade endocannabinoids?
hydrolysis or oxidation
how is anandamide degraded via hydrolysis?
Fatty acid amide hydrolase (FAAH)
how is 2AG degraded via hydrolysis?
mono-acyl glycerol lipase (MAGL)
how are both AEA and 2AG degraded via oxidation?
cyclooxygenase and lipooxygenase pathway
