Ligand-Gated Ion Channels & G-Protein Coupled Receptors Flashcards
Cells communicate with each other using ________ which elicit changes in the ________ of the target cell.
- Chemical messengers
2. Enzymatic activity
Ligand-gated ion channels and G Protein Coupled receptors are found where?
In the plasma membrane of many cells.
Membrane receptors are vital for?
Cell to cell communication
LGIC and GPCR are sensors for what kind of signals?
Extracellular
When signals are transmitted across a membrane by LGIC and GPCR how does the cell respond?
The cell interprets the signal and then the appropriate response occurs.
If receptors are like sensors, the signals that they respond to are called ______. If the signal activates the receptor it is an ______. If it inhibits activation of the receptor it is called an _________.
- Ligand
- Agonist
- Antagonist
What kind of cells are LGIC and GPCRs found on?
Almost every cell in the body including excitable cells like the ones in nervous system.
Action potentials are characteristic of what kind of cells? (name 4).
- neurons
- muscle cells
- cardiac cells
- some glands
Propagation of APs from one cell to another is vital for?
Cell-to-cell communication.
The first step in propagation from one cell to another is?
The activation of ligand-gated ion channels
Once a LGIC causes a channel to open and the membrane depolarizes, the depolarization activates what? Which results in what?
- Voltage gated ion channels to open
2. Allows more ions to flow across the membrane and the action potential continues to propagate down the neuron
Are LGIC excitatory or inhibitory? What does this mean?
- They can be either.
- Meaning that they will either increase the probability or decrease the probability of an action potential in the cell.
What dictates whether an ion channel is excitatory or inhibitory?
What kind of ions the channel passes through the membrane.
Reducing the difference in charge between a membrane is known as?
Depolarization
The flow of negative ions into a cell is known as?
Hyperpolarization
The excitatory versus inhibitory classification is true for which types of ion channels/pores?
All of them, not just the LGICs.
What is the rate of transmission of LGICs?
Very fast, approx. milliseconds.
Agonist binding does what to a LGIC?
Opens the pore
Name the two major families of LGICs.
- Cys-loop receptors
2. Inotropic glutamate receptors.
Name three types of cys-loop receptors.
- nicotinic acetylcholine receptors
- GABAa receptors
- glycine receptors
Name three types of inotropic glutamate receptors.
- AMPA receptors
- NMDA receptors
- Kainate receptors
Inotropic glutamate receptors are receptors that pass ions and are named for the?
Drugs that specifically activate them.
What kind of drugs work on cys-loop receptors? (name 5).
- Nicotine
- Varenicline (chantix)
- muscle relaxants (succhs)
- anti-epileptic drugs
- anxiolytics.
Barbiturates and other anti-epileptic drugs and other drugs used to treat anxiety act how at what receptor?
As agonists on the GABAa receptor (which is a cys-loop)
How many subunits does each cys-loop receptor have?
5.
Each of the 5 subunits of the cys-loop receptor have how many transmembrane domains?
4.
Which of the 4 transmembrane domains in the cys-loop receptor is responsible for forming the ion poor?
2nd.
What are the five types of subunits on a cys-loop receptor and what two things do they affect?
- alpha, beta, gamma, delta and epsilon.
2. They affect how quickly and what types of ions can pass through the receptor.
How many alpha subunits does a cys-loop receptor have to have?
2.
Where does the ligand bind to the cys-loop receptor?
Binding is between the alpha subunit and it’s neighbor subunit.
Nicotinic acetylcholine receptors and serotonin receptors (cys-loop) are what kind of receptor in regards to their specificity? What kind of ions do they allow to pass? Does this make them excitatory or inhibitory?
- non-specific cationic channels
- Mostly Na and K, sometimes Ca.
- Excitatory
Glycine receptors and GABAa receptors (cys-loop) conduct which ion? Does this make them excitatory or inhibitory?
- Chloride
2. inhibitory (hyperpolarizing)
Why are nicotinic Ach receptors vital to physiology? (name 3).
Because they are present in the CNS, all ganglionic synapses of the ANS, and the neuro-muscular junction.
In an inactive state, the second transmembrane domain of the alpha subunit (in a cys-loop receptor) bows in causing what? This explains the concept of?
- Obstruction of the pore.
2. Gating
Agonist binding to BOTH of the binding sites causes what to happen? Be specific.
The receptor to be activated. The receptor is activated because the alpha subunit changes conformation in a way that twists the kinked second transmembrane domain out of the way, opening the channel.
What activates AMPA, NMDA and kainate LGIC receptors (they’re all glutamate receptors)
Glutamate
What ions do the LGIC glutamate (AMPA, NMDA and Kainate) receptors pass? Are they inhibitory or excitatory?
- Na and K, NMDA can pass CA
2. Excitatory (depolarizing)
How many subunits do the glutamate (AMPA, NMDA and Kainate) LGIC receptors have?
four subunits.
How many transmembrane domains does each the four glutamate LGIC receptor (AMPA, NMDA and Kainate) subunits have?
Four
Where is the pore formed in the glutamate LGIC receptor?
Formed by the second transmembrane receptor domain.
Each subunit of the glutamate LGIC has how many binding sites? Are they all for glutamate?
- Each subunit has a binding site, so four, binding sites.
- No, not every binding site is for glutamate. (ex: in NMDA receptors two of the four binding sites are for glutamate and the other two are for glycine- all four binding sites must be occupied for the channel to open)
Glutamate is the predominant ________ neurotransmitter in the mammalian brain.
Excitatory.
At resting membrane potential, NMDA (part of the glutamate subfamily of LGICs) receptors are blocked by what?
Magnesium.
The magnesium which blocks the NMDA (part of the glutamate subfamily of LGIC) receptors is dependent on what? What causes it to move? Besides the removal of the magnesium which one other condition must be met for the NMDA channel to open.
- Voltage
- When the post-synaptic cell is depolarized (which happens after AMPA receptors are activated by glutamate)
- It must also have a glutamate bound to it.
When the NMDA receptors (part of the glutamate subfamily of LGIC receptors) transmit Ca2+ what do they activate? What does this activation cause?
- Activates CaMKII
2. More AMPA receptors
NMDA receptors are coincidence receptors meaning what?
A way to tell when when a neuron has fired multiple times
Most synaptic transmission is mediated by what kind of receptor?
AMPA
Are GPCRs faster or slower at signalling compared to LGICs?
Slower
What is another name for GPCRs?
7 transmembrane receptors
How many genes do we have for GPCRs?
over 800, 3% of our genome
How many main classes of GPCRs are there?
- A, B & C.
Which class of GPCRs are the most common?
A
What types of receptors are included in Class A GPCRs? (2)
adrenergic and muscarinic acetylcholine receptors
What types of receptors are included in Class B GPCRs?(1)
parathyroid hormone receptor
What types of receptors are included in Class C GPCRs? (2)
metabotropic glutamate receptors
GABAb receptors.
What kind of drugs act on GPCRs? (name 3)
- beta adrenergic receptor antagonists
- beta adrenergic receptor agonists
- mu opiod receptor agonists
(beta blockers, asthma meds and opiods)
When the GPCR is activated it binds to what?
Alpha subunit of trimeric G protein.
Once the alpha subunit is bound to the GPCR it replaces ______ for ______? Because of what?
It replaces GDP for GTP because of a conformational change caused by the agonist occupying the receptor.
Once activated by GTP what happens to the alpha subunit?
It dissociates from the beta and gamma subunits and goes on to activate effector enzymes.
Once effector enzymes are activated by the GTP activated alpha subunit what is produced?
Second messengers.
The alpha subunit of the G protein has intrinsic GTPase activity meaning that over time what will happen?
It will hydrolyze its bound GTP into GDP + inorganic phosphate becoming inactive.
What does the inactive GDP-bound alpha subunit do?
It will reassociate with the beta and gamma subunits.
Once the alpha subunit has reassociated itself with the beta and gamma subunit what happens to the receptor?
It is ready for another round of signalling.
Receptor activated G proteins are bound to which side of the cell membrane?
The inside of the cell membrane
How many main types of G alpha subunits are there? What is the difference between these?
- 3
2. The different alpha subunits change what enzyme the activated G-protein activates.
Second messengers activate what? leading to what?
- A second level of enzymes
2. Different cellular responses
What are the three main types of G alpha subunits?
Alpha q, alpha s and alpha i.
Alpha q subunits (of GPCRs) activate what effector enzyme?
phospholipase C
Activation of phospolipase C (by the alpha q subunit) causes what to occur?
Hydrolysis of phosphoinositol (PIP2)
The hydrolysis of phosphoinisitol (PIP2) caused by the activation of phospolipase C (PLC) by the alpha q subunit results in an increase of what two second messengers?
DAG and IP3
What does the increase in IP3 (second messenger resulting from the alpha q activation of PLC and the resulting hydrolysis of PIP2) cause?
The release of CA2+ from intracellular stores.
What does DAG (second messenger resulting from the alpha q activation of PLC and the resulting hydrolysis of PIP2) cause?
It can activate protein kinase C which phosphorylates other proteins causing them to be activated (gene expression).
What effector enzyme does the alpha s subunit (of GPCRs) activate?
Adenylyl cyclase
When alpha s is coupled to Adenylyl cyclase it takes _______ and converts it into what second messenger?
- ATP
2. cAMP
The second messenger cAMP (converted from ATP by adenylyl cyclase after being bound to alpha s) results in an activation of what?
PKA.
Once activated by cAMP, PKA is responsible for what?
Like PKC, phorsphorylates other proteins causing them to be activated (gene expression)
PKA (activated by cAMP) and PLC (activated by DAG) may have the same job but what is different about them?
They are responsible for different gene expression and transcription factors.
What effector enzyme does the alpha i subunit (of GPCRs) inactivate?
Adenylyl cyclase
GPRC activation has ________ cellular outcomes.
Diverse.
G protein activation of effector enzymes produce second messengers that do what?
Modulate the activity of many other enzymes.
When will GPCR desensitize?
After prolonged exposure to an agonist.
Receptor desensitization partially explains what phenomenon?
Drug tolerance
What deactivates a G protein from it’s receptor if it has been activated for too long?
beta-arrestin.
How does beta-arrestin bind to the receptor to deactivate the G-protein?
once a receptor is activated by its agonist for long enough it will cause a second slower conformational change in the receptor allowing for the binding of beta-arrestin. Once bound the beta-arrestin physically forces the G-protein away preventing it from being active.
The process of beta-arrestin deactivating the G protein is known as what? and why?
Desensitization because a beta-arrestin bound receptor is no longer sensitive to the agonist (meaning it can no longer mediate G-protein signaling)
Other than the act of desensitization, why else is beta-arrestin important?
Because it is a protein scaffold meaning that it acts as a dock for other important proteins.
What type of important proteins (general) does beta-arrestin dock?
Those used for the internalization of receptors.
With even more prolonged exposure to the agonist, the receptor bound to beta-arrestin complex will become what?
Internalized.
Once the receptor-beta-arrestin complex is internalized what two things could happen to it?
It is either sent to the lysosome to be degraded or acts as a scaffold for other proteins involved in cell signalling
If a receptor-beta-arrestin complex is internalized and degraded by a lysosome what does this mean for the receptor?
It is totally broken down so receptor activity is prevented until new receptors are produced.
If a receptor-beta-arrestin complex is internalized and used as a scaffold for signalling it is called what?
Beta arrestin dependent signaling.
Why is it useful for proteins to be scaffolded inside the cell by the receptor-beta-arrestin complex?
Brings them close together which makes them activate each other more efficiently
What are the three broad types of GPCR signaling? What is the time between them.
- G-protein signaling and then seconds to minutes until
- beta-arrestin binds causing desensitization and then minutes until
- beta-arrestin-dependent activation of signaling cascades.
If a drug activates on pathway more effectively than another it is a?
Biased ligand.
Niacin, an effective treatment for high cholesterol, activates what receptor? What is a side effect that limits its use? What mediates the cholesterol lowering effect? What mediates the flushing effect?
- Gi-coupled receptor GPR109A (I will never actually care/remember this but it was on the slides)
- Flushing
- G protein mediated
- B-arrestin mediated
