Flashcards in Ionotropic Receptors & Neuromuscular Junction Deck (94):
In the Nicotinic acetylcholine receptor (nAChR), where is the binding site for ligand?
How many molecules of ACh need to bind to nAChR to open channel?
Current through a channel depends on what two factors?
driving force and conductance
I = g(Vm-Veq)
Current - Voltage relationship (I-V curve) tells you these three properties:
1. Equilibrium (Reversal) potential / ion selectivity
2. Channel conductance
What two ligand-gated cation channels are similar to nicotinic receptor?
AMPA and Kainate channels
What type of channel is NMDA receptor?
Ligand-gated and voltage-gated
What type of receptor is GABA
Ligand-gated choride channel
Chloride channels are usually (inhibitory/excitatory)
Synaptic effects of ionotropic channels are (excitatory/inhibitory)
They can be either
What determines whether opening the channel is excitatory or inhibitory?
The reverse (equilibrium) potential
If the reversal potential is (greater/lesser) than the action potential threshold, it is excitatory
Channels that form ion channels
Describe how ligand-gated ion channels work
Two neurotransmitters (ligands) bind to channel, channel opens, lets ions through (ligand-gated ion channel)
Two main classes of neurotransmitter receptors
1. Ionotropic receptors
2. Metabotropic receptors
How can you broadly define metabotropic receptors?
Includes any receptor that does not directly form an ionic channel membrane, can have intracellular/second messenger signaling and downstream effects
What is the largest class of metabotropic receptors?
3 important properties of a single subunit of the nicotinic acetycholine receptor
1. 4 transmembrane domains
2. Large extracellular and intracellular tails, regulate activity of channel
3. N and C terminal tails are outside the cell
nAChR can have different subunit variations in different parts of the brain and nervous system. These composition variance can have strong effects, a major one being what?
Nicotine binding strength
What lines the pore of the nicotinic receptor structure?
Transmembrane domain number 2 (TM2)
Why do variations in subunits affect binding strength?
Binding unit infringes on parts of subunits, not completely on alpha
What is the function of an ionotropic receptor?
To change the membrane potential of a cell, which will have consequences for signaling of cell
Does the ionotropic receptor have an electric property?
Yes, have to understand current that flow through channels and how they affect membrane potentials
Relationship between membrane potential and current, specifically for membrane potential:
V = IR
Relationship between membrane potential and current, specifically for ionic currents:
I = g(Vm-Veq)
g = conductance = 1/R
What is the driving force?
The difference between membrane potential and equilibrium potential; the greater the difference, the greater the driving force
Another name for equilibrium potential
Patch clamp measurement of a single ACh receptor shows what type of current?
Show step like current as goes from open to closed state- when closed, no conductance/current
What does size of current depend on?
STRICTLY the conductance and driving force, not ACh
What determines the open state of channel?
ACh determines its open state, but has NO EFFECT on size of current.
A whole cell recording of synaptic current
A more pointed current. less step like because not all open or closed at same time, represent current flow into and out of cell
In the I-V curve, what is the x and y axis?
x axis: V (mV) voltage
y axis: I (pA) current
If reversal/equilibrium is at 0, then the channel is permeable to multiple ions (no single ion has nernst potential of 0). What is this type of channel called?
non-selective cation channels
Where on graph can you determine the reversal/equilibrium potential?
When there is zero current (point intersecting with x-axis)
In the I-V curve for nicotinic receptor channel, is the conductance voltage independent or dependent?
Voltage independent. Get straight line, instantaneous slope will be same, so conductance is same no matter what voltage is.
What affect conductance in a nicotinic receptor channel?
Only the present of ACh. Voltage does not affect conductance, because you get a straight line when look at I-V curve.
What does voltage determine in a nicotinic receptor channel?
Voltage determines size of current because determines driving force.
3 subtypes of ionotropic glutamate receptors (excitatory)
AMPA, kainate, NMDA (these three are agonists for the neurotransmitter glutamate)
P2X purinergic receptor
What 3 other receptors are in the same gene family with nAChR?
5-HT3 (serotonin receptor), GABA, glycine
Glutamate binds to what three types of cation ion channels?
1. AMPA receptor
2. NMDA receptor
3. Kainate receptor
glutamate activates all of these but have different functional properties
Two options for subunits of ionotropic glutamate receptor channels
1. 4 transmembrane helices
2. 3 transmembrane helices plus pore loop
What ionotropic glutamate receptor channel(s) are similar to nicotinic receptors?
How are AMPA and Kainate receptor channels similar to nicotinic? (3)
1. Reversal (equilibrium) potential = 0 mV
2. Channel is permeable to SODIUM, POTASSIUM, and calcium
3. Voltage independent (positive linear slope)
Two special properties of NMDA receptor ion channel
1. both ligand-gated and voltage-gated
2. high calcium conductance (relatively high permeability to calcium)
Glutamate is not sufficient to open the NMDA receptor channel due to the presence of this:
magensium ions present in extracellular space, physically lock the channel
In order for the NMDA channel to open even with glutamate present, it requires this additional stimulus:
Membrane potential, or voltage
What causes Mg to get kicked out of its position blocking the channel?
Depolarization of cell. Voltage sensor in channel causes conformational change
NMDA receptor channel-dual requirement of glutamate and sufficient depolarization
Importance of NMDA receptor's high permeability to calcium
not just electrical property (because Ca or Na can do this)-more important is that Ca2+ can act as secondary messenger, makes it in a way a metabotropic receptor
Nernst potential for chloride is similar to?
(More/Less) Cl outside cell than inside cell
If open Cl channel, Cl moves (into/out of) cell
Into cell. Will try and move potential to 0.
GABA receptor is what type of ligand gated channel?
Glycine receptor is what type of ligand gated channel?
Cation, inhibitory (similar to GABA except it uses cations)
GABA is a site for many different drugs; the drugs bind to the (same/different) site as GABA
Examples of types of drugs that can bind to GABA receptor (4)
Benzodiazepine, barbiturates, steroids, and picrotoxin. Alcohol and barbiturates have synergistic effects on channel, cause increased depression. Can overdose
Definition of excitatory input
Increase probability/frequency of action potential
The type of transmission at a given synapse, Excitation vs inhibition, is determined by the (receptor/transmitter)
Receptor. (dependent on reversal potential of that channel relative to action potential threshold)
Why are reversal potentials not necessarily constant?
Reversal potential is determined by Nernst equation, if concentrations of ion are changing, that will affect the potential. These concentrations vary base on cell type or development.
In the developing brain, GABA is (Excitatory/inhibitory)
Excitatory. In Adults (mature neurons), it's INHIBITORY.
Why is GABA excitatory in early development?
1. High [Cl] inside cell,
2. Reverse potential higher than its normal -80 (closer to 0)
3. When GABA receptor channel opens, Cl leaves cell
4. Depolarization (not relevant to excitatory)
5. Reversal potential > threshold = excitatory
True or false: While GABA receptor in mature neurons is inhibitory due to low intracellular [Cl-], some parts of brain maintain high [Cl].
True. This is why it's important not to look at neurotransmitter to determine whether excitatory or inhibitory, but rather to look at the receptor.
Ionotropic receptor (ligand gated ion channels)
metabotropic receptor (often G-protein coupled receptors)
Structure and function of neuromuscular junction:
Transmitter = ?
Post synaptic receptor = ?
Transmitter activation = ?
Post synaptic effect = ?
Nicotinic ACh receptor
Enzymatic- acetylcholinesterase in the synaptic cleft
Excitatory, elicits muscle contraction, each endplate potential leads to an action potential and contraction
What does each quanta refer to?
A single vesicle of neurotransmitter
How do individual quanta leave the presynaptic terminal?
This auto-immune disorder shows signs of muscle weakness, especially with sustained activity, and ptosis
What does myasthenia gravis target?
Targets the nAChR in neuromuscular junction, post synaptic target
Three examples of disorders of neuromuscular transmission that are presynaptic targets
1. Lambert Eaton Myasthenic Syndrome (LEMS)
2. Botulinum toxin
3. Tetanus toxin
What does LEMS target?
antibodies targeted to presynaptic calcium channels, frequent complication of small cell carcinomas
What does botulinum toxin target? What does it cause?
Protease produced by clostridium bacteria cleave SNARE proteins essential for presynaptic vesicle fusion
causes muscle weakness, respiratory failure
What does tetanus toxin (also from clostridium) target? What does it cause?
Blocks release of inhibitory transmitter (glycine) in spinal cord. Causes hyperexcitation and spastic (tetanic) contractions
electrical synapse is (flexible/inflexible)
inflexible-not a lot of ways of modifying this transmission
4 functional examples of electrical synapse. Describe.
1. Escape responses-reflex actions, need to form rapidly and reliably
2. Neurosecretory cells- cells that release bolus of hormone, need to release synchronously
3. Glial cell network-calcium signaling (particularly astrocytes)
4. inhibitory neurons that regulate cortical rhythms (GABA)
Property of chemical synapses where strength of synapse can be strengthened or weakened. Important for learning and memory throughout life
Why are chemical synapses unidirectional?
Because they depend on specialized mechanisms (can occasionally have retrograde where goes in opposite direction)
These 4 neurotransmiters use GPCRs exclusively:
2. Serotonin (EXCEPT 5-HT3)
These 4 neurotransmitters use both ionotropic and metabotropic receptors:
A single synapse can have (only one/multiple) receptor subtypes
Why is a single end plate potential (EPP) not smooth in recording?
Because when release ACh, muscle cell becomes depolarized, gets close to equilibrium potential (@ 0 mV for nicotinic receptors), and get extra amplification from Na voltage channels.
Is a single EPP large enough to exceed an AP threshold for muscle contraction?
Yes. When a motor neuron fires, it releases enough ACh to release a signal large enough to produce an AP. Every time a motorneuron fires, muscle cell will fire an AP.
What produces miniature endplate potentials? (MEPPs)
Spontaneous release of transmitters from synaptic vesicles. They occur constantly, vague role in maintaining synaptic strength
What changes MEPP frequency?
Changes in pre-synaptic release probability
What changes size of MEPPs?
Changes in postsynaptic receptor (decrease in function or number)
AChE inhibitor, increases synaptic levels of ACh
In an EMG recording of muscle action potentials in a patient with Myasthenia gravis, we see APs that have decreased in size. If APs are defined as "all or none," how can you explain this?
The reason we see decrease is because its a compound of action potentials that are being fired synchronously. If half of fibers are not contracting, contributes to overall decrease in size.
In LEMS, you see (increased/decreased) efficacy of transmission in exercise
Increased. If getting more stimulation during exercise (aka repeated APs being fired), some channels aren't blocked, little bit of calcium can add up and can reach level for release of transmitter.
Symptoms of LEMS are similar to what other disorder?
Myasthenia gravis. Also in both cases, get reduced end plate potential, reduced depolarization.
In measuring MEPPs, you would expect to see reduced (frequency/amplitude) in Myasthania Gravis, and reduced (frequency/amplitude) in LEMS
MG- reduced amplitude (post-synaptic problem in ACh receptor)
LEMS- reduced frequency (pre synaptic problem with calcium channels)
This disorder is associated with small cell lung cancer and other carcinomas
How does botox work?
Example of botulinum toxin. Wrinkles are caused by constant contraction of small muscles of face. Botox cleaves SNARE proteins essential for vesicle fusion in motor neuron terminals, causes muscle weakness and relaxes them.
removes excitatory input (muscle is always excitatory)
Irreversible Acetylcholinesterase inhibitors
Nerve gas, pesticides - Sarin