Chemical Messengers And Excitotoxicity Flashcards
What are the presynaptic channels?
Presynaptic voltage gated gated calcium channels
What do presynaptic voltage gated calcium channels do?
Allows calcium to come in and bind at docking proteins
What are inotropic receptors?
Ligand gated ion channel
What are metabotropic receptors?
Activated G protein
What are IPSPs?
What is this assoc. w/?
Small, localized hyperpolarizations
Chloride entry
What are EPSPs?
What is this assoc. w/?
Small, localized depolarization
Assoc.w/ Na or Ca entry
What is temporal summation?
Where does it occur?
Multiple IPSPs or EPSPs elicited from DIFFERENT synapses
Post synaptic cells
What is spatial summation?
Multiple IPSPs and EPSPs elicited from REPETITIVE activation at the SAME synapse
What happens when a cell reaches threshold?
An action potential occurs
What kind of receptor is a
Nicotinic cholinergic R.?
Ligand gated ion channel (ionotropic)
How many subunits does a nicotinic cholinergic r. Have?
5 subunits
What does a ligand binding a nicotinic cholinergic r. Do?
Ligand binds —> conf. Change in pore —> allows ions to enter
What causes the selectively of nicotinic cholinergic rs?
Charge of AAs that make up the pore
Size of the pore
What are metabotropic receptors also known as?
Serpentine
What codes for metabotropic receptors?
1 gene
What produces the variations in metabotropic receptors?
Post translational modifications
Have many membrane spanning domains do metabotropic receptors ahve?
7
How do metabotropic exert post synaptic effects?
Via 1 or more secondary messengers
What are the 2 major types of G proteins associated w/ intracellular domain of metabotropic Rs?
Gs
Gi
What do Gs proteins do?
Activate adenylate cyclase
Increase production of cAMP from ATP
CAMP interacts with PKA
PKA phosphorylates downstream targets and changes activities
What effects can Gs have?
Have effects on protein synthesis at level of gene due to existence of CREB
(cyclic amp response element binding protein)
What does Gi do?
Inhibit adenylate cyclase
Decrease cAMP and PKA activation
What does Gq do?
Activate phospholipase C
Creates IP3 and DAG
IP3 activates Ca release
What will Ca do?
Calcium influences cellular functions
Calcium can work with DAG and activate protein kinase C —> further phosphorylates other proteins
What is the Jak-Stat pathway?
Receptors with tyrosine kinase that activates its dimer when a ligand binds
What will activation of Jack stat pathway cause?
Active dimer activates associated kinase and autophosphorylates the receptor
then phosphorylates STAT protein
STAT dimerizes and goes to nucleus
Activates synthesis of various proteins
What does retrograde transport cause for rabies?
The 1-3 mo. Long incubation period fo rabies
What are the requirements for NTRs?
Neuron making NTR had proper machinery
NTR is released in a chemically or pharmacologically identifiable form
Exogenous application of NTR reproduces post-syn. Effects
Blocking receptor for chemical will block effects of activating pre-synaptic neuron
Mechanism for termination exists
What is the cholinergic system?
Where is it prevalent at?
Any synapse that uses ACh
Peripheral nervous system
What uses the cholinergic system?
Alpha motor neurons at NMJ
What is cholinergic input critical for?
What could damage cause?
To being conscious
Comatose state or development of Alzheimer’s diseae
Where do we see ACh as a NTR in the PNS?
NMJ Autonomic preganglionic synapses Parasym. Post-g fibers Symp post-g fibers to sweat glands/muscles Amacrine cells in retina
Where do we see ACh as a NTR in the CNS?
Striatum
Brainstem arousal
How is acetylcholine made?
Acetate CoA + choline
Via choline acetyltransferase
Gives: acetylcholine
What move ach into vesicles for a controlled release?
Vesicular ACh transporter protein (VAChT)
How do you break down ACh?
Acetylcholinesterase hydrolyzes ACh back to acetate and choline
Choline recycled by presynaptic cell
Acetate diffuses away
What are the receptors of the cholinergic system?
Muscarine
Nicotinic
What activates the muscarine receptors for smooth muscle cells and glands?
What blocks it?
Muscarine
Atropine
What are the 5 types of muscarine receptors linked with?
G proteins
M1 - Gq M2 - Gi M3 - Gq M4 - Gi M5 - Gq
Where are M1 Rs?
What do they do?
Post -g neurons of ans, broadly distributed
Increase IP3, DAG, Ca
Where are M2 Rs?
What do they do?
Decrease cAMP —> increase K conductance —> hyperpolarization
Where are M3 Rs?
What do they do?
Smooth muscle of bronchi and vasculature
Will increase IP3 and DAG
Where are M4 Rs?
What do they do?
Presynaptic autoreceptors
Control ACh release in Striatum of basal ganglia for motor control
Decrease adenylate cyclase —> decrease cAMP
Where are M5 Rs?
What do they do?
Cerebral vasculature
On basal ganglia dopaminergic neurons
For motor controls
Increase IP3 and DAG
What are the 2 subdivisions of nicotinic receptors?
NMJ
Neuronal
How many subunits make up a nicotinic receptor?
5 subunits each from a different genes
Can be homo or heteromeric
What is the make up of fetal NMJ AChRs?
2 alpha
Beta
Gamma
Sigma
What i the make up of adult NMJ AChRs?
2 alpha
Beta
Gamma
Epsilon
The changed subunit allows for more sodium entry and thus a larger conductance
What do high ca conductance or neuronal NMJ AChRs. Contribute to?
Are these metabotropic or ionotropic?
Ionotropic
Learning and memory
What are all the NTRs in the monoamine system from?
Created by modifying AAs
What are the catecholamines of the monoamine system?
Epi
NE
Dopamine
What are the 5 NTRs making up the Monoamine system?
Epi NE Dopamine Serotonin Histamine
What is epi, NE, and dopamine all derived from?
Tyrosine
How do you synthesize catecholamines?
‣ Tyrosine + tyrosine hydroxylate**—> L-DOPA
= rate limiting step
‣ L-DOPA + L-DOPA decarboxylase —> Dopamine
‣ Dopamine + enzymes(assoc. w/ intracellular vesicular membrane) —> NE
• NE actually synthesized within vesicles
‣ NE leaves vesicle + Phylethanolamine-N-Methyl-transferase (PNMT)*** —> Epi
What 4 major pathways use Dopamine?
- Substantia nigra dopaminergic pathway
- Mesolimbic dopaminergic pathway
- Mesocortical dopaminergic pathway
- Tuberinfundibular pathway
What is the role of dopamine?
What is damage assoc. with?
Role in producing pleasure and addiciton
Parkinson’s disease
What is the Mesolimbic dopaminergic pathway?
What could alteration of this pathway cause?
From ventral tegmental area to nucleus accumbens
Core of pleasure/reward pathways in brains
Addiction
Where is NE found within the CNS?
Locus ceruleus in upper brainstem (Pons)
What is the role of NE?
Waking us up (!!!!!) and awareness
Produces inhibition of msucle activity that occurs during REM sleep
Where is Epi mostly used?
Used as hormone released by adrenal medulla
Not really used in the CNS
How are catecholamines stored?
Via vesicular monoamine transporters (VMATs) catecholamines are moved into vesicle where they will be stored
(And where NE will be created)
Where is VMAT 2?
Neuronal form found in any neuron that releases monoamines
VMAT 1 found in adrenal medulla
What do NE and E bind to ?
Alph and beta adrenergic Rs which are mediated by 2nd messenger system
What is the second messenger system associated with alpha 1, 2 ,and betas?
Alpha 1 - Gq
Alpha 2 - Gi
Beta 1,2,3,- Gs
QISSS
What is the receptor for dopamine?
Dopaminergic receptors with differerent subtypes D1-5
Where do we find high concentrations of receptors D1 and D2?
What are they involved in?
In regions of brain innervated by substantia nigra
Involved in normal control of motion and emotion
How are catecholamines removed?
Dopamine, NE and E are all removed via
High affinity uptake protein then enzymatic destruction by MAO or COMT
What is serotonin derived froM?
Tryptophan
Where is serotonin found in brainstem?
Raphe nuclei
What is serotonin for?
Critical in mood
How is serotonin synthesized?
‣ Typtophan + tryptophan hydroxylase —> Rate limiting step
amt. of Trypt. Available and activity level of enzyme determines amt. of serotonin)
‣ ___ + 5-HT Decarboxylase —> serotonin
Where are seronergic neurons in the CNS?
Midline raphe nuclei use serotonin as NTR in CNS
Serotonin from midline raphe nuclei control what?
What could disruption cause?
Attention and mood
Depression
What are serotonergic receptors associated with?
All associated with G proteins
EXCEPT 5-HT-3
what is the only ionotropic serotonergic receptor?
What is it assoc. w?
5-HT 3
Opens sodium channel
Assoc. w/ chemotactic trigger zone in medulla
What is the role of 5-HT6?
High affinity for several anti-depressants
What is the role of 5-HT2c?
Controlling normal body weight and preventing seizures
How is serotonin removed?
Taken up and metabolized by MAO
What is histamine derived from?
Histidine
What i the role of Histamine
Waking you up (!!!!)
What wakes you up?
What keep you awake?
Norepinephrine
Histamine
Where is histamine made and released in the CNS?
By neurons of tuberomammillary body/nucleus in the posterior thalamus
What are the purines that serve as NTRs?
ATP
AMP
Adenosine
What do purine NTRs bind to?
Purinergic receptors
What purine is linked to sensation of sleepiness/fatigue?
Adenosine
Where is caffeine an antagonist at?
Adenosine receptors
How are purine NTRs removed?
Via adenosine Deaminase
Converted to inosine and removed via circulation
Where does adenosine bind?
P1 receptor
What is the function of adenosine?
Sleep induction
Feedback inhibition for atp release
What are the 5 groups of peptides that bind opioid receptors?
Endorphins Enkephalins Dynorphins Endomorphins Nociception
What are opioids associated with?
All except which one?
Pain relief
Except for nociceptin
Where are opioid NTRs located?
Striatum
Hypothalamus
Periaqueductal gray
Nucleus parabrachialis
Raphe nuclei (serotonin also here!)
What is the pre-cursor to dynorphins?
Where are they found?
Prodynophrins
hypothalamus
Thalamus
Brainstem
Retina
What will nociceptin produce?
Produces pain
What are the 3 receptors of opioid NTRs?
Mu
Kappa
Delta
What does the Mu opioid receptor produce when activated?
Analgesia
Respiratory depression
Euphoria
What does the Kappa opioid receptor produce when activated?
Analgesia
Dysphoria
What does the Delta opioid receptor produce when activated?
Analgesia
All of the opioid receptors are paired with what and cause what?
Gi
Cause inhibition of adenylyl cyclase
Mu- increases k out = hyperpolarization
Kappa and Delta = decrease Ca in
What are the 2 ligands that bind cannibinoid receptors?
Anandamide
2-arachidonoylglycerol
What is the endocannibinoid system assoc. with?
Pain relief actions
Control of hunger and energy balance
May produce neuroprotection
What blocks the uptake of endocannabinoids?
Acetaminophen
How is anandamide and 2-AG metabolized?
Cyclooxygenase
Lipooxygenase
What does the CB-1 receptor bind?
Anandamide and 2AG
What does CB2 preferentially bind ?
2-AG
What is the production of NO tied to?
Activation of excitatory AA receptor - NMDA
What are inhibitory AAs?
Glycine
GABA
How do inhibitory AAs enact their actions?
Open Cl channel and produce hyperpolarization of membrane
What is the major inhibitory AA of the brain?
GABA
Where does benzodiazepene work to produce sensation?
GABA Receptors
What are the major EAAs in the brain?
Glutamate
Aspartate
What is the role of EAAs?
Sensory processing
Memory formation
Learning
Motor control
What do EAA Receptors allow for?
Allow ca to enter cell
What is excess activation of the EAA system associated with?
Neuronal damage via excitotoxicity
What is GABA made from?
Glutamate + GAD
Where is gaba localized? Glycine?
GABA - cerebellum and cortex, and retina
Glycine: Spinal cord mostly
What has the most extra-synaptic receptors? Why?
GABA
Bc it is the most inhibitory and will hyperpolarized neurons non specifically for sedation
For the EAA system, what is the role of glycine and glutamine?
Glutamine forces Mg off the receptor allowing for docking to occur and glycine is needed for the channel to work:)
What is the majority of atp created by neurons used for?
To drive Na/K ATPase pump to help maintain RMP
What happens is oxygen or glucose to the brain is blocked?
What could cause blockage potentially?
No ATP = no maintenance of RMP = depolarization of brain = AP for a short period of time with NTR release
Stroke, drowning, cardiac arrest
What will the depolarization of the brain inadvertently cause?
Will produce APs
Release NTRs (EAAs)
Xs activation - xc Ca entering = Ca binds enzymes and changes activity
What can huge amounts of calcium entering a post synpatic cell cause?
Will bind enzymes and change activity
Lead to production of NO
Release arachidonic acid damaging membrane
Hydrolyzed proteins
Activate apoptotic enzymes
What are the receptors for EAAs?
Metabotropic or ionotropic?
NMDA
non-NMDA
Both ionotropic
What do NMDA receptors do?
What binding sites do they have?
Open channel for Ca to enter (and Na)
Glycine
Zinc
PCP
MG
What binding side of NMDA receptors is needed to have an Epsp occur?
Glycine
What does the PCP binding site of NMDA receptors do?
Blocks calcium current from inside the channel
What does the Mg binding site of NMDA receptors do?
Inside the channel and blocks it
What needs to be removed from a NMDA receptor in order for an epsp it occur?
Mg
What are two non-NMDA receptors for EAAs?
AMPA r.
Kainate R.
How are EAAs removed?
By astrocytes and neurons
Can use Na dependent 2ndary active transport
High affinity system
Loss of Na gradient
What is Rasmussuen’s encephalopathy?
What receptor is it assoc. w?
Severe intractable seizures that develop in a child and can cause brain damage that destroys one hemisphere of the brain
NMDA r.
How is production of NO tied to activation of the EAA receptor NMDA?
NMDA will allow calcium in
Lead to calcineurin activation which will cleave a phosphate group from NOS activating it
NOS + arginine = NO
What are the actions of nitric oxide?
Induce guanylyl cyclase and form cGMP
CGMP will relax smooth muscle, change presynaptic neuron for long term potentiation or depression
What are the roles of NO?
Major controller of cerebral vasculature bc it dilates vasculature
How is NO removed from the synpase?
No uptake mechanisms bc it is too lipid soluble
Hemoglobin could potentially bind but not likely
What is the only rate limiting factor of NO?
It’s half life (5 seconds)
What kinds of brain damage is excitotoxicity linked to?
Domoic acid poisoning from contaminated muscles
Hypoxia or anoxia
Cerebral ischemia/stroke
Mechanical trauma to the CNS
Hypoglycemia
What is the sequence of events for excitotoxicity?
- Ischemic insult
- Increased intracellular calcium
- Activation of enzymes by calcium
- Deranged cellular metabolism
- Induction of apoptotic pathways
What happens as a result of ischemic insult?
Rapid reduction in ATP levels leading to cell depolarizaiton, release of NTRs, activation of Non-NMDA and NMDA receptors, further increase of EAA concentration in synapse
What happens once NMDA receptors are activated by the ischemic insult?
Allow xs calcium into cell and voltage gated calcium channels to open
After the ischemic insult activates NMDA and that increases intracellular calcium,
What effects does calcium have?
Activates
Phospholipase A2
Calcineurin —> NO
Mu-Calpain(protease)
Maybe enzymes for an apoptotic cycle
What happens as a result of enzyme activation from calcium?
Concerning phospholipase
Phospholipase will act on cell membranes
Release arachidonic acid
Act on intracellular organelles to cause more Ca release
organelles will malfunction (ER will unfold and activate kinases)
What happens as a result of enzyme activation from calcium?
Concerning mu-calpain
Mu-calpain
Damages structural and functional proteins within the cell and inhibits protein synthesis
What happens as a result of enzyme activation from calcium?
Concerning calcineurin
Activates NOS
Produces xc NO
How are apoptotic pathways induced during excitotoxicity?
High Ca will disrupt the mitochondrial membrane
Releases cyto c and caspase 9
Activates caspase 3 —> major proteolytic enzyme associated w/ apoptosis
What happens when one tries to restablish blood flow following an ischemic insult?
Reperfusion injury
What happens in a reperfusion injury?
Blood gives oxygen to tissues
Neurons take it up and mito. Uses it to make atp
But leftover is made into peroxide radicals
Peroxide radicals damage lipids, membranes, organelles
Blood also delivers blood borne chemicals
During a reperfusion injury what are the blood borne chemicals being reintroduced into the brain?
Epinephrine - further depolarizes cell and activates PKA
White blood cells- further calcium influx
Growth factors - no funct. Organelles to respond to this
What happens as a result of calcium activating calcineurin which makes excess NO?
NO will cause vasodilation and smooth muscle relaxation
Allows for influx of fluid into damaged areas and causes EDEMA
Increased ICP - blood flow compromised - tonsillar and uncal herniations can develop
What are some treatments for excitotoxicity?
Block EAA neurotransmission
Prevent influx of WBC
Uptake Ca
Free radical scavenger
What are the 2 important things concerning excitotoxicity?
Time (cascade initiated too quickly)
Scope of treatments (not wide enough)
(Also drugs that would be delivered via blood cannot happen bc of ischemic event)
(Cells are damaged and cannot respond to drug)
Denervation hypersensitivity occurs when the alpha–motoneuron innervating skeletal muscle is transected. The muscle cell begins to respond to any acetylcholine, whether it is at the neuromuscular junction or not.
What is the mechanism for this response?
When there is no synaptic activity, Nicotinic cholinergic R. At motor end plate is released
migrates away and may come into contact with Ach from non neural sources
becomes activated and produces AP/contraction in sk. M. In absense of intention
appear as twitches or fasciculations of muscle rather than organized contractions
What contributes to the variations in processes seen after an ischemic event?
Genetic difference of non-NMDA and NMDA receptors that change amt. of cations entering the cell
Depressants in s system can lead to better neurological outcomes
How do systemic hypothermia and induced comas improve neurological outcomes/survival of people who have different brain injuries?
Metabolism by neurons is decreased
Reduced o2 demand
Decreased APs = decreased NTR
Decreased enzyme activity (caspases)
Can use Valium (benzodiazepene) to activate GABA and produce inhibitory effects in brain or act on non-NMDA AMPA receptors to reduce flow thru them and allow for less Na and Ca in cell (hyperpolarizing)
