Lecture 16-18 Flashcards
Curare (5)
From + what + mechanism + wrong usage + high doses
- From tropical american woody plants
- Skeletal muscle relaxant
- Blocks Ach Receptor
- 1942-curare to supplement conventional anaesthesia (used in surgery then discovered wrong usage)
- High dose affects breathing
Acetylcholine in PNS and CNS (2)
- In the PNS it triggers muscle contraction and stimulates the sectretion of hormones (ex: growth hormones)
- In the CNS it works as a NT for wakefulness, anger, aggression, attention, sexuality, thirst, memory
Acts in synapse between motorn neurons and muscles
Neurons that synthezise ACh:
cholinergic
Ach precursors and synthesis enzyme:
- Choline: From fat in diet
- Acetyl CoA: produced by metabolism of sugar and fats
- Catalyzed by choline acetyltransferase (ChAT) enzyme
Acetyltransferase (ChAT) enzyme (2)
What + inhibit
- Transfer acetyl group from acetylcoA to choline
- inhibit CHAT then no acetylcholine
Rate of synthesis for ACh is controlled by (2):
- Availability of precursors
- Rate of cell firing
ACh is loaded into synaptic vesicles by: (3)
what + where + inhibited by
- Vesicular Ach transporter (VAchT)
- In the membrane of vesicles
- Vesamicol inhibits VACht and reduces ACh release. ACh cannot be packaged and gets broken down by enzymes
Black widow spidwer venom (a-latrotoxin) (2)
What + how
- stimulates massive ACh release
- forms pores on membrane in the lipid membrane causing influx of Ca2+ and ACh release
Clostridial bacteria (clostridium botulinum) (5)
o2 + ACh + muscular + lethal dose + treatment/used for
- Anaerobic
- inhibits ACh release
- muscular paralysis: asphyxiation (breating muscles affected)
- Lethal dose 0.3 ug
- Treatment of spasm in eyelid, face and botox (temporarily paralyze muscles to reduce wrinkles by blocking ACh)
ACh breakdown
- Acetylcholinesterase (AChE) breaks down ACh into choline acetic acid
- Choline is taken back into the presynatptic neuron via choline transporter.
AChE inactivation (reversible)
Three exampls
- More acetylcholine remaining at synapse
- Donezepil, rivastigmine, galantamine for treatment of Alzheimers Disease
- Physostigmine for treatment of glaucoma.
- Neostigmine, pyridostigmine do not cross BBB. Used in treatment of autoimmune disorder myasthenia gravis (reduce ACh breakdown so more is at synapse.
AChE inactivation (irreversible)
occurs bc + 2 examples
- Occurs because of colvalent bond between enzyme (AChE) and themself
- organophosphorous compounds: Insecticides such as parathion malathion
- Nerve gases- used in chemical warfare:
Sarin gas was colourless, odourless liquid and causes death from asphixation
Antidote for Sarin gas:
- Atropine: antagonists of muscarinic ACh receptors (blocks receptor, save time)
- Pralidoxime Chloride: breaks covalent bond of sarin to AChE
Potential causes of Gulf War Illness (3):
- Pyridostigmine Bromide: thought to increase efficacy of nerve agent antidote (reversible AChE inhibitor)
- Organophosphates: Pesticides used to keep pest-borne diseases low
- Sarin gas exposure
Cholinergic neuron locations (3)
- Interneurons in striatum (motor control)
- Basal Forebrain cholingergic system (memory and, cognitive function)
- Tegmental nuclei in pons, mesencephalon (sleep/wake/arousual/attention)
The two types of ACh receptors:
- Nicotinic receptors
- Ionotropic
- Ion channels: ACh binds, ion enters, depolarization
- Increaed neuronal firing, muscle contraction - Muscarinic receptors
- Metabotropic
Nicotinic Receptors (6)
subunit + alpha + function + most expressed + enhance + eliminate response
- 5 subunit around a central core
- alpha subunit is the essential one, without it, receptor will not form
- subunit composition affects function.
- a2B2 makes most widely expressed receptor in cortex
- a5 affect function of channel by enhancing. Knockout reduces nicotinic response
- B2 knockout eliminates nicotinic response
Functional states of nicotinic ACh resceptor (3):
- In the abscence of agonist, (ACh/nicotine), receptor is in closed state
- Upon ligand binding, receptor is in open state
- Prolonged exposure leads to desensitized state. Receptor remains closed even though ACh/nicotine is present. lots of agonist bound for a long time, channel has to go through re-sensitization
Depolarization block (2):
what + example (what + receptor kind + resistant + conitnous + depol)
- Persistent depolarization of the cell membrane, cell cannot be excited anymore until you remove the agonist.
- Ex: succinylcholine
1. Nicotinic-ACh receptor agonist
2. powerful muscle relaxant (cant move in surgery)
3. Resistant to AChE
4. Continous stimulation of nicotinic receptor
5. depolarization block of muscle cell
D-tubocurarine (7)
what + ingredient for + muscle + death + treated with + used to treat + BBB
- nicotinic ACh receptor antagonist
- main ingredient of curare
- high affinity for muscle nicotinic receptors
- death by respiratory paralysis
- treated with anti-AChE drugs
- used to treat black widow venom as it block nicorinic receptors
- little BBB penetrance so small affect on CNS cholingeric neuron
Muscarinic receptors (3)
- metabotropic
- 5 different types
- G-protein coupled (Gs/Gi)
PFC neurons (3)
what + the two responses
- have both nicotinc and muscarinic AChRs Give ACh activtes both receptor
- ACh binding to nicotinic receptor causes excitation/depolarization
- ACh binding to muscarinic receptor is a slower response and you need more (g-protein)
Loss of —- rewarding effect of morphine is lost
- M5 receptor function (cannot activate dopamine neurons)
Give me an example of ACh pathway:
mAChR agonist (2)
Examples + symptoms
- muscarine, philocarpine, arecoline
- sweating, tearing, salivation, highly constricted pupils, contraction of smooth muscles, cardiovascular collapse, coma, death
mAChR antagonist
Examples + symptoms
- atropine, scopolamine
- restlessness, irritability, disorientation, hallucinations, delirium, respiratory paralysis, coma, death
inhibit cholinergic transmission
Glutamate (3)
what + abundant in + what makes it
- main excitatory transmitter in CNS
- Most abundant in all neurons and glial cells
- glutamerneurogic neurons and other neurons make glutamate
Gluatamate synthesis from —- is catalyzed by the —–
- glutamine
- glutaminase enzyme
Gluatamate is packaged into vesicles by (3):
- the Vesicular glutamate transporter (VGLUT1-3)
- VGLUT1: Cortical region
- VGLUT2: Subcortical region
- VGLUT3: Not in brain
How is glutamate stored/released (3)?
with who + 2 methods
- Can be stored and released as a co-transmitter (glutamate and dopamine, glutatmate and 5-HT etc)
- Co- release: dopamineurogic neuron that can release glutamate , stored in the same vesicle and released from AP at same time
- Co-transmission: in different vesicles
—- can also release glutamate
GABA
How is glutamate processed after release?
- Reuptake by excitatory amino acid transporters (EAATs 1-5)
- Pre/post neurons can take up glutamate on their own
- Astrocytes also release and take up glutamate via EAAT1 or 2 (gliotransmission)
- In astrocytes glutamate is converted to glutamine by glutamine synthetase
- Glutamine is released by astrocytes and picked up by neurons
Prolonged high levels of glutamate in synapse produces :
excitotoxicity
EAAT2 knockout mice:
- epileptic seizures
- increased susceptibility to seizures/brain injury
- Shorter lifespan (excess glutamate)
Glutamate vs Glutamine
- glutamine is less toxic and used as a safer way to store
Glutamatergic pathways are the main —– pathways throughout the brain. It is involved in ——— functions and is important for ——, ——, —-,
- excitatory
- all behavioural and physiological functions
- synaptic plasticity, learning and memory and cell death
Glutamate receptors types (2)
- Ionotropic (fast)
- AMPA receptor, Kainate receptor, NMDA receptor - Metabotropic (slow)
Glutamate Ionictropic receptors (4)
ex + response + composed + ion
- AMPA, Kainate, NMDA
- All produce an excitatory response
- Each is composed of a different set of subunits (4 subunits)
- All allow Na+ into the cell but NMDA can allow Na+ and Ca2+
NMDA receptor (4)
ion + how to open
- Allow the flow of both Na+ and Ca2+
- To open the channel, both glutamate and glycine or D-serine (co-agonists) must bind at the same time.
- Mg2+ ions block the channel pore at resting state.
- Mg2+ ions dissocate when membrane is depolarized (AMPAR receptor)
NMDA receptor antagonists
- Non-competitive: PCP. ketamine (for depression), MK-801, memantine (mild-moderate alziemers)
NMDA antagonist can mimic —–
schrezophenia
Anti-NMDA receptor encephalitis
- Autoimmune disorder, and patient makes antibody against their own NMDA receptor, bind to it and cause less on the membrane
Metabotropic glutamate receptors:
how many + the diff ones + excit/inhib + post/presynaptic
- mGluR1-8 (8 diff GpCR)
- Group 1: mGluR1, 5 activates phosphoinositide 2nd messenger system (PLC, Ca2+). These are postsynaptic and mediate excitatory response.
- Group 2: mGluR2, 3 inhibit cAMP.
- Group 3: mGluR4,6,7,8 inhibit cAMP
- Group 2/3 Mostly presynaptic, function as autoreceptors for glutamate release. If heteroreceptor they inhibit the release of glutamate.
Ampakines (6)
what are they + enhance + what they do to receptor + monkey + rats + humans
- cognitive enhancers
- enhance glutamate action on AMPAR
- modulate AMPAR receptor activity (open longer)
- In monkey delayed match to sample task, their performance increased (cursor to star)
- In Rats treated with 3 months with Ampakines, they had increased dendritic length and spine formation.
- In humans, it didnt improve cognition in adult treatment
Long term potentiation (LTP)
- High frequency signals, repeated stimulations (ex: studying or revising) of neurons are strengthened repeatedly and release glutamate that acts on post-synaptic receptors cause strengthen of synapse.
- synchronous activity increase strength of synaptic communication
Explain the process of what happens when glutamaneurgic neuron is stimulated (LTP):
- When glutamerneurgic neuron is stimulated, action potential cause release of glutamate
- It binds to postynaptic receptors
- AMPA and NMDA receptor often co-exist. Weak stimulation cause small amount of glutamate to release, NMDA will not be activated first (needs depolarization), AMPAR will be activated first.
- Opening of AMPAR cause depolarization as large amount of Na+ influx
- Strong stimulus cause AMPAR to be open for a longe time, stronger depolarization, removing the mg2+ block in NMDA allowing Ca2+ and Na+ to enter.
- Ca2+ is the LTP inductor
Early LTP (3)
independent + Ca2 (3) + basis of
- Protein synthesis independent (no gene affected)
- Ca2+ initiate signalling pathway that activate other protein kinase that enhance synpatic communication such as
- phosphorylating AMPA receptors which increase Na+ conductance such as making it open longer
- increase postsynpatic AMPARs by receptor trafficking (the intracellular movement of receptors from sites of synthesis to the plasma membrane, where they function, and then to sites of degradation) - Basis of short term memory (last several hours)
Late LTP (3)
+ duration
- New proteins are made, gene expression further enhances synaptic connection
- Newly synthesized AMPARs and other proteins (dendritic spine growth, synaptic connection)
- Formation of long-term memory (lasts for days/month)
In general, increases in AMPAR function at synapses result in the ——- of synaptic strength, whereas removal of synaptic AMPARs leads to ——-.
- long-term potentiation (LTP)
- long-term depression (LTD)
Co-transmission can be split into 2 subtypes:
- Differential Ca2+ sensitivity: NT in different vessicals and have different sensitivity. One might need multiple AP and the other one only one.
- Spatial Segregation: 1 AP release them both at different synaptic butons and post-synaptic sites.
Excitotoxicity hypothesis for Glutamate:
Excessive exposure to glutamate (or kainate, NMDA) leads to prolonged depolarization of receptive neurons that can lead to damage or cell death.
Domoic acid (4)
What is it + activates + causes + animal example
- Excitatory amino acid acting as a neurotoxin
- Activates glutamate receptors
- Causes dizziness, confusion, muscle weakness, loss of short term memory and sometimes death
- Birds slamming in house windows due to marine algae blooms producing domoic acid eaten by fish then the birds
Glutamate excitotoxic brain damage can occur with brain ischemia (interruption of blood flow from stroke or heart attack). This can cause: (3)
cause what + treating it
- Rapid cell death in the core due to lack of oxygen. You cannot recover from this.
- Can also cause depolarization in penumbra which is the peripheral tissue. O2 deprivation is only partial so there is hope there can be recovery. Depreivation in penumbra causes massive release of glutamate and prolonged activation of glutamate receptor (NMDA).
- To treat u can give NMDA antagonist to block it.
Glutamate excitotoxic brain damage is hypothesized to occur in —— such as —–. The only treatment is —– which involves ——.
- neurodegenerative disease
- ALS
- Riluzole
- reducing glutamate release by binding to VG Na+ channels to prevent AP propagation.
GABA (3)
NT + synthesized in + made from…by
- Predominant inhibitory transmitter in CNS
- Synthesized in GABAergic neurons
- Made from glutamate, catalyzed by glutamic acid decarboxylase (GAD)
GABA is packaged into vesicles by
- vesicular GABA transporter (VGAT)
can also transport glycine
GABA released as co-transmitter (2):
- Can be stored and released as a cotransmitter with Gylicine or glutamate
- In general inhibitory with glycine co-released
- With glutamate more fine-tuning synaptic networks. In different synaptic vessicles.
GABA reuptake (3):
transporter + by what + enzyme
- Reuptake by GAT1-3
- Both neuronal and astroglial uptake via GATs
- GABA is metabolized to glutamate and succinate by GABA aminotransferase (GABA-T) in GABAergic neurons and in astrocytes they are released and uptaken by neuron through GATs. Remade through GAD to make GABA again.
Anti-convulsant drugs for GABA (3)
what it does + 2 examples
- Increased GABA in synapse
- GABA-T (metabolizing enzyme) irreversible inhibitor: Vigabatrin
- GAT-1 inhibitor: Tiagabine (inhibit GABA transportor so less reuptake)
Convulsant drugs for GABA (2)
what it does + 2 examples
- Block GABA synthesis
- GAD inhibitor: allyglycine, 3-mercaptopropionic acid
Low amount of GABA results in:
- less inhibitory tone in brain
- enhanced excitability
- Seizures
GABA receptors: ionotropic (3)
Name + activation causes + subunit
- GABA A receptor
- Activation of it causes Cl- ions to enter the cell causing fast hyperpolarization and inhibition
- 5 subunit
GABA receptors: Metabotropic (3)
Name + activation causes + subunit
- GABA B receptor
- Activation causes Gi/o activation, cAMP inhibition, opening of K+ channels and hyperpolarization and inhibition
- Most common subunit composition is (a1)2(B2)2(y2)
GABA A receptor agonists
- Muscimol
GABA A receptor antagonists (2)
comp + noncomp
- Competitive: Bicuculline
- Non-competitive: Pentylenetetrazol picrotoxin
block GABA
GABA A Allocsteric modulator (5):
what it does + increase + potency + DRC + examples
- enhance receptor function and allow it open for longer (need to have GABA binded already tho)
- Increase inhibitory tone not at GABA binding site
- Potency of GABA increase
- DRC shifts left
- Ex: Benzodiazepines, barbiturates, ethanol, propofol, neurosteroids
GABA B receptors (4)
types + post + pre + both
- autoreceptors and postsynaptic
- Postsynpatoc: Inhibition of neuron firing by opening K+ channels
- Presynaptic: Inhibition of transmitter release by inhibiting Ca2+ channels (inhibits cell that GABA comes from aka Autoreceptors)
- Both: inhibition of adenylyl cyclase and cAMP formation
GABA B receptor agonist and competitive antagonist:
- competitive antagonists: Saclofen, 2-hydroxysaclofen
- Agonists: Baclofen (muscle relaxant)
Anesthetics and receptors (2):
- more Cl- to enter
- Block NMDA receptor and cell’s ability to fire
