GPCR and Ligand-Gated Channels Flashcards
Name two receptors found in the plasma membrane of many cells.
ligand-gated ion channels and G protein coupled receptors
Action potentials are transmitted from one neuron to the next by release of __________
neurotransmitters
Neurotransmitters are released from the presynaptic neuron and then activates _____.
ligand-gated ion channels on the post-synaptic neuron and ions then flow into the cell.
What happens if you get several ligand-channels activated?
if enough of these channels are activated, you will get a big change in the membrane potential, depolarization, and this activates voltage gated channels to open
What channel propagates action potentials?
voltage gated
At resting membrane potential the inside of the cell has an overall __________ charge compared to the outside of the cell.
negative
If a ligand activates the receptor it is called an______
agonist
If a ligand inhibits activation of the receptor, it is called _______
antagonist
Ligand-gated ion channel can be ____ or _______
excitatory or inhibitory
What is the definition of excitable cell?
where ions can flow across its membrane, causing reversible fluctuations in the electrochemical gradient across the cell membrane (action potential)
Depolarization
occurs when positive ions flow across the membrane
Refractory period
another AP cannot be triggered during this time
What is the first step in propagation from one cell to another?
activation of ligand-gated ion channel
What dictates excitation vs inhibition?
the kind of ions the channel passes thru the membrane
Define an excitatory ion channel.
passes positive ion into the cell, thus reducing the charge difference between outside and inside the cell–>depolarization
What ion would pass through an excitatory ion channel?
Na+, K+, Ca++
Define inhibitory ion channel.
passes negative ions into the cell and increases the charge difference between the outside and the inside the cell —> hyperpolarization
What ion would pass through an inhibitory ion channel?
Cl-
How quick is the transmission of a ligand-gated ion channel?
milliseconds, once the ligand binds to the receptor
What are the major families of ligand-gated ion channels?
cys-loop receptors and ionotropic glutamate receptors
What are some examples of Cys-loop receptors?
nicotinic acetylcholine receptors, GABAa receptors, glycine receptors
What are some examples of ionotropic glutamate receptors?
AMPA receptors, NMDA receptors, kainate receptors
What is the predominate inhibitory neurotransmitter in the brain?
GABAa
Where are nicotinic acetylcholine receptors found?
in all ganglia, at the NMJ, and in the brain
Glycine receptors are also _______.
inhibitory
What is the predominate excitatory neurotransmitter in your brain?
glutamate
What are examples of some drugs that act on Cys-loop receptors?
nictoine, varenicline (chantix) muscle relaxants (succhs) anti-epiletpic drugs, anxiolytics (barbits, diazepam)
What are some exmaples of drugs that act on glutamate receptors?
aniracetam
“smart drugs”
ketamine
Drugs used to treat anxiety are GABAa receptor __________.
agonists
Succhs interferes with what receptors?
nicotinic acetylcholine receptors signaling at the NMJ causing depolarizing neuromuscular block and short-term muscle relaxation
Ketamine, aside from its use as an analgesic, is an NMDA receptor _________.
antagonists
How many subunits make up a cys-loop receptor?
five
Each subunit has how many transmembrane domains?
4
The subunit composition affects how _____ and what types of ______ can pass through the receptor.
quickly; ions
No matter what a cys-loop receptor always as to have how man alpha subunits?
2
The binding site for the ligand is between an ______ and its ______ subunit
alpha and its adjacent
Why is the composition of the subunits important?
it dictates what passes through
What do nicotinic acetylcholine receptors and serotonin receptors have in common?
excitatory non-specigic cationic channels - pass mostly Na+ and K+, sometime Ca++
What do glycine and GABAa receptors conduct?
Cl-
In an inactive state, the second transmembrane domain of the alpha subunit…
bows in, obstructing the pore
What swings the transmembrane domain out of the way?
agonist binding
T/F: Both binding sites must be occupied by ACh in order for the receptor to be activated.
True
How many subunits make up a glutamate receptor?
4
Each subunit of glutamate receptor has how many transmembrane domains?
4; pore is formed by the second transmembrane
T/F: In a glutamate receptor each subunit has a binding site.
True
Are all four binding sites for glutamate?
No, for NMDA receptors, two binding sites are for glutamate and two are for glycine.
Do all four binding sites have to be occupied for the channel to open?
YES
What ions for glutamate receptors pass?
Na+,K+
What receptor can conduct Ca++?
NMDA
Does the second transmembrane domain completely cross the membrane?
No, it enters and then comes back
At resting membrane potential, NMDA has a binding site for what ion?
Mg++
What does Mg++ do at the receptor?
it blocks voltage-dependent; sits in the pore and keeps all other ions out
What kicks out the Mg++?
glutamate is bound to the receptor and the post-synaptic neuron becomes depolarized
Once Mg++ is kicked out, what ion can pass through and why is it important?
NMDA transmits Ca++ which is a signaling ion and binds to proteins.
What is one of the important proteins that Ca++ binds to an activates?
CaMKII
What is one of the downstream affects of CaMKII?
causes more AMPA receptors to be inserted on the cell making the cell more excitable
NMDA receptors are “______ ______”
coincidence receptors; a way to tell when a neuron has fired multiple times
When you learn something or form a new memory, whats happening?
more AMPA receptors inserted on the cell making the cell more excitable
What is long-term potentiation?
long-lasting enhancement in signal transmission between two neurons that results from stimulatory them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength. - Major cellular mechanisms that underlies learning and memory
Are G protein-receptors (GPCR) faster or slower at signaling than ligand-gate ion channels?
slower
What are the 3 main classes of GPCR?
What are some examples of each class?
Class A: adrenergic receptors, muscarinic acetylcholine receptors
Class B: parathyroid hormone receptor
Class C: metabotropic glutamate receptors, GABAb receptors
How many transmembrane domains do GPCR have?
7
What are examples of some drugs that act on GPCRs
beta-blockers (b-adrenergic receptor antagonists)
asthma meds, salbutamol (b-adrenergic reeceptor agonist)
opioids (mu-opioid receptor agonists)
What is going on at the resting state of a GPCR?
GPCR and associated g-protein are inactive which means the associated g-protein is bound to GDP
What 3 subunits are bound the the g-protein?
alpha - binds GDP
beta-gamma subunit- inhibits the alpha subunit and prevents it from interacting with GTP
What happens when the GPCR is activated?
An agonist binds to te receptor, causes a conformational change in the receptor which forces the beta-gamma subunit away. When the beta-gamma subunit goes away, now the alpha subunit can replace is GDP with GTP. Once GTP is bound the alpha subunit is active and it goes on to activate other proteins that are downstream.
How does the receptor inactivate itself?
Once it’s bound long enough, the alpha subunit will hydrolyze the attached GTP to GDP by its inherent enzymatic activity, allowing it to re-associate with beta-gamma subunit starting a new cycle.
What protein acts to accelerate the hydrolysis of GTP to GDP?
a group of proteins called Regulator of G-protein signaling, act as GTPase-activating proteins, specific for alpha subunits
Gq-coupled alpha subunit
activates phospholipase C - enzyme that cleaves lipids in the cell membrane. So it leaves PIP2 into IP3+DAG - these are two signaling molecules (called second messengers)
IP3
binds to receptors on the ER and causes Ca++ to be released from ER into the cytoplasm. - Ca++ can also be a signaling molecule
DAG
activate other enzymes - protein kinase C - this enzyme phosphorylates other proteins which causes them to be activated and this does things like phosphorylates transcription factors which turns on genes and causes gene expression
Gs-coupled alpha subunit
coupled with adenylate cyclase - takes ATP and coverts it into cAMP (second messenger). cAMP activates protein kinase A which is similar to protein kinase C - which will phosphorylate downstream proteins like transcription factors and cause gene expression
Do PKC and PKA phosphoralate the same transcription factors?
No
Gi-coupled alpha subunit
inhibit the action of adenylate cyclase
Why is generation of second messengers important?
activation of one G protein can lead to the production of many second messengers, so it is a way to amplify the receptor signal
Receptor Desensitization
- GPCR will desensitize after prolonged exposure to agonist
- Receptor desensitization partially explains why drug tolerance develops
What happens if a an agonist is bound long enough to a GPCR?
it will cause a second, slower conformational change in the receptor. This new receptor confirmation allows for the binding of a protein known as B-arrestin. This kicks the alpha subunit away from the receptor - the receptor cannot be activated even if an agonist is bound to it.
What happens if desensitization prolongs?
Beta-arrestin is a protein scaffold, this means it acts as a dock for other important proteins. Some of the proteins that can dock onto beta-arrestin include proteins involved in internalization of receptors.
What are two events can happen if a receptor is internalized?
sent to the lysosome and be degraded or these vesicles can act as scaffolds for other proteins involved in cell signaling
Beta-arrestin-dependent signaling
GPCR-beta-arrestin complex acts as a scaffold for signaling. This is another signaling pathway that occurs when GPCR are activated. Scaffolding of proteins brings them close together, which makes them activate each other more efficiently.
When does down-regulation occur?
when internalized receptors get degraded
Biased ligands
when a drug activates one pathway more effectively than another
What is an example of a biased ligand?
MK-0354: G protein-biased agonist
g-protein mediated - cholesterol lowering effect
no flushing d/t no beta-arrestin
