Exam 2: Topic 5 P2 Flashcards
how is NMDA current in the absence of glutamate and Mg2+? glutamate and Mg2+? glutamate but no Mg2+?
- in the absence of glutamate and Mg2+ there is no current
- in the presence of glutamate and Mg2+ there is current with depolarization
- Mg2+ is blocking still ⇒ with Mg2+ there is no current below threshold - in the presence of glutamate but absence of Mg2+ current is according to DF
- With no Mg2+ there is current even at hyperpolarized states
what happens when there is both AMPA-R and NMDARs on a plasma. membrane?
Fast opening of AMPA-Rs cause depolarization that removes the Mg2+ block off NMDA-Rs
what happens when AMP-R is missing but NMDA-R is present?
Removing AMPA-R from a synapse will silence the NMDA-R because they cannot open in response to glutamate
- needs AMPA to change the voltage threshold so Mg2+ will leave
T/F NMDA is a voltage gated channel?
False
it has some degree of voltage sensitivity, but is not a voltage gated channel
when do NMDA receptor open voltage-wise?
when Vm > Erev
- At rest the NMDA receptor is blocked by magnesium
- Glutamate is also binding to AMPA so when glutamate binds this cell will have a rush in of sodium which kicks out the magnesium on the NMDA receptor allowing for calcium to come into the cell
what 2 things are needed for NMDA receptors to open?
- glutamate presence
- depolarization
then calcium can come into the cell via the NMDA receptor while AMPA will only let Na+ in (and K+)
Silent synapses
inactive during baseline neurotransmission until after AMPA-R are inserted, where they become active with baseline neurotransmission
- Presynaptic cell releases glutamate but the postsynaptic cell doesn’t respond to it
how do we test what is causing silent synapses?
we stimulate a presynaptic neuron to release glutamate and monitor potential on the postsynaptic cell for a response
- if the postsynaptic cell has membrane potential above threshold and you stimulate, then you get a response telling us the NMDA receptors are probably becoming activated
- There are no AMPA receptors at the beginning of the developmental stage but there are NMDA receptors ⇒ you need AMPA to kick out the NMDA magnesium block
glutamate excitotoxicity
caused by continued (over) excitement of the NMDA receptors
- Leads to high levels of intracellular calcium and eventually cell death via apoptosis ⇒ calcium comes in and kicks off cell processes
- The large influx of calcium stays inside the cell ⇒ cell can’t keep up or maintain
what conditions lead to excitotoxicity?
- ischemia (oxygen deprivation) in stroke, drowning, during birth (cerebral palsy)
- Brain trauma
how do you reduce excitotoxicity?
- Blocking NMDA-R ⇒ no longer lets calcium in
- Activating postsynaptic voltage gated potassium channels and hyperpolarizing the cell
how many main classes are there of metabotropic glutamate receptors?
3 and have different functions
1. activates PCL
2. inhibits adenylyl cyclase
3. inhibits adenylyl cyclase
how is GABA synthesized? (Enzyme)
glutamate ⇒ GABA (gamma aminobutyric acid) by glutamic acid decarboxylase (GAD) enzyme
what is the packaging for GABA?
into vesicular GABA transporter (VGAT) and diffuses through synaptic cleft
what is the reuptake of GABA?
GABA transporter (GAT) by neurons and glial cells
what is GABA-A?
Ligand gated Cl- channel that legs Cl- through
what is GABA-B?
GPCR that activates K+ channels and inhibit Ca2+ channels
- Hyperpolarizes by reducing Ca2+ coming in and K+ goes out
how many subunits does GABA-A have?
heteropentamer so it has 5
what ions go through GABA-A?
Cl- and is usually hyperpolarizing
what are agonists of GABA-A?
Benzodiazepines, Barbiturates, Steroids
what are antagonists of GABA-A?
strychnine (plant toxin), picrotoxin (snail toxin) block channels
what happens when GABA is released into the synapse?
when measuring changes in the cell with firing frequency, the postsynaptic neuron is inhibited for a while before GABA is taken back up into the cell
NKCC GABA-A receptor
used in early development for Na+, K+, Cl- cotransporter
- Na+ with gradient
- Cl- and K+ against gradient
when is NKCC activated?
when Erev > threshold
- the GABA-A receptor sends Cl- ions out of the cell because Cl- is high inside the cell and low outside
- this is excitatory
KCC GABA-A receptor
used in later development for K+ and Cl- co-transporter
- K+ with gradient
- Cl- against gradient
when is KCC activated?
when Erev < threshold
- the receptor sends Cl- inside the cell since the outside concentration is much higher at this point
- this is inhibitory
for GABA-A receptors, ECl- > threshold leads to?
excitation (depolarization) and AP
for GABA-A receptors, ECl- < Vrest leads to?
inhibition (hyperpolarization)
for GABA-A receptors, ECl- > Vrest but < threshold leads to?
a depolarization but not reach threshold so no AP
- Depolarizing inhibitory threshold potential
how is glycine synthesized?
serine becomes glycine via serine hydroxymethyltransferase
binding for glycine
NT receptor binding with NT on receptor and off
packaging for glycine?
vesicular inhibitory amino acid transporter (VIAAT)
reuptake of glycine?
glycine transporter (GlyT) leads to re-uptake by neurons and glia
- we don’t know what happens when it gets taken up by glia yet
T/F glycine has only GPCR channels?
False
- Ligand gated Cl- channel similar to GABA-A only
what is the typical synthesis pattern of catecholamines?
start off as tyrosine ⇒ dopa ⇒ dopamine ⇒ norepinephrine ⇒ epinephrine (from 1 precursor you get all 3 catecholamines)
- Then we get specialized neurons for each type of catecholamine based on enzymes in the neuron
what are the transporters for catecholamines?
vesicular monoamine transporter (VMAT)
what is the binding for catecholamines?
NT receptor binding GPCR on and off
what is the reuptake of catecholamines? (3)
NT receptor binding on GPCR goes to two sides
- Dopamine transporter (DAT)
- Norepinephrine transporter (NET)
- Epinephrine transporter (we don’t know)
how is cocaine related to catecholamines?
blocks reuptake of DAT which increases dopamine present
how does degradation of catecholamines work? (2)
- Monoamine oxidase (MAO)
- Catechol O-methyltransferase (COMT)
what do monoamine oxidase inhibitors do (MAOIS)?
blocks the breakdown of catecholamines
T/F catecholamines have ligand gated receptors?
False only GPCRs
what areas of the brain make dopamine and what does this do?
SNc and VTA midbrain ⇒ goes many place in the brain and does project to spinal cord
- Motor control
- Motivation
- Reward
- Addiction
what areas of the brain make norepinephrine and what does this do?
locus coeruleus midbrain/pons ⇒ many regions of brain including cerebellum and spinal cord
- sleep/wake
- Arousal
- Attention
- Feeding
what areas of the brain make epinephrine and what does this do?
medulla ⇒ limited regions of the midbrain
- Respiration
- Cardiac function
- Locomotion
what is the synthesis of serotonin?
tryptophan ⇒ 5-hydroxytryptophan ⇒ 5-hydroxytryptamine (other name for serotonin)
what is the packaging for serotonin?
vesicular monoamine transporter (VMAT)
what is the binding for serotonin?
NT receptor binding GPCR and ionotropic
- on and off receptor
what is the reuptake of serotonin?
Serotonin transporter (SERT)
- Selective serotonin reuptake inhibitors (SSRIs) bind here and blocks the serotonin transporter to prevent reuptake as fast which helps with depression
what is similar about MDMA binding to serotonin?
MDMA aka ecstasy also binds SERT ⇒ reuptake inhibitor which makes you feel happy
what is the degradation of serotonin? (2)
- Monoamine oxidase (MAO)
- Catechol o-methyltransferase (COMT)
what areas of the brain make histamine and what does this do?
hypothalamus ⇒ all parts of the nervous system projection
- Arousal
- Attention
- Allergic reactions
what areas of the brain make serotonin and what does this do?
Raphe nuclei midbrain/pons and project to many areas of the brain like midbrain, cortex, cerebellum, and spinal cord
- Circadian rhythm
- Anxiety/depression
- Locomotion (modulation)
how purines synthesized?
glycolysis, aerobic respiration, etc.
how are purines packaged?
vesicular nuclear transporter (VNUT)
how does binding work for purines?
NT receptor binding on and off receptor (both types)
- ionotropic
- GPCRs
what type of ionotropic receptors do purines have?
P2X receptors
- trimers that are excitatory nonselective cation channels
what type of GPCR receptors do purines have?
- P1 (A1-3): receptors prefer adenosine
- P2Y: receptors prefer ATP
what happens after binding for purines? (2)
- Degradation to adenosine
- Re-uptake
what is the synthesis of neuropeptide NTs like?
transcription ⇒ translation ⇒ proteolytic processing/modification
what is the packaging of neuropeptide NTs?
packaging into dense core vesicles and diffusing through the synaptic cleft
how does binding for neuropeptides work?
NT receptor binding on and off receptor
what happens after binding for neuropeptides? (2)
- Degradation
- Re-uptake
endogenous opioids
dynorphins, enkephalins, endorphins that bind to GPCRs
- Mu, Delta, Kappa (MOR, DOR, KOR)
- Very potent ⇒ only small amounts required
morphine
agonist for opioid receptors
methadone
treatment for morphine and heroid addiction
endocannabinoids
endogenous signals derived from phospholipids ⇒ lipid soluble
types of body synthesized endocannabinoids? (2)
- Arachidonoylglycerol = 2-AG
- Anandamide = AEA
plant derived endocannabinoids?
Tetrahydrocannabinol = THC
- much more stable than bodily endocannabinoids and thus can have a more potent or long lasting effect
what are endocannabinoids dependent on?
Synthesis in postsynaptic cells is 2nd messenger dependent
- signal retrogradely to reduce pre-synaptic release
what type of receptors do cannabinoids have?
CB1 and CB2 GPCR’s
what is the synthesis of endocannabinoids? (enzyme)
phospholipids turned to 2AG or AEA via diacylglycerol ligase (DAGL)
what is the packaging for endocannabinoids?
N/A can’t do it
- diffuse through synaptic cleft either anterogradely or retrogradely
what is the binding of endocannabinoids
NT receptor binding GPCR on and off receptor
what is the pathway after binding for endocannabinoids? (3 players)
degradation by FAAH, MAGL, or COX2
- Fatty acid amide hydrolase (FAAH)
- Monoacylglycerol lipase (MAGL)
- Cyclooxygenase 2 (COX2)
properties of NO? (3)
- Highly diffusible (10s of microns) gas produced by NO synthase
- Coordination of population of cellular activity
- Acts on guanylyl cyclase which produces cGMP
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