Receptors Flashcards
What is the purpose of the Food and Drug administration (FDA)?
To approve or reject applications from drug companies to market new drugs; old drugs which fail to meet, purity, safety or efficacy standards may be removed from the market
Purpose of the Drug enforcement Administration (DEA)
To establish a balance between legitimate medical needs while minimizing the availability of the drug for abuse
Purpose of the 1970- Comprehensive Drug abuse, Prevention and Control Act (Controlled substances Act)
Regulates the manufacture, distribution, dispensing, use and possession of all CNS drugs with abuse potential with the exceptions of alcohol and tobacco
What schedule of drug has the highest abuse potential?
C-1 (illegal drugs)
What schedule of drug has the least abuse potential?
C-V (gabaproteins)
What is an example of C-I drugs?
Illegal drugs like heroin, LSD, marjuana, mescaline, phencyclidine (PCP)
What is an example of C-II schedule drugs?
Morphine, methylphenidate
What is an example of C-III schedule drugs?
Tylenol #3 (codeine mixtures)
What’s an example C-IV schedule drugs?
Benzodiazepines (for people with insomnia)
What are some examples of C-V schedule drugs?
Gabapentin, some codeine-containing cough syrups
What are some things that can be receptors?
Enzymes, proteins, nucleic acids
What are most receptors? Why?
Proteins
- undergo 3D structural changes
- have spatially and energetically favorable molecular domains for binding
What do true receptors elicit?
A biological response when bound by an agonist
How must the interaction (binding) between drug and receptor be?
Selective binding of drug to biological target before a response can take place
A drug will elicit a biological response when?
When bound to an agonist
What are inert binding sites?
Places where a drug can bind, but there will be no biological response elicited
Example of plasma proteins; what kind of binding sites do these have?
Albumin; Inert binding sites (drug can bind to albumin but it won’t elicit a biological response)
What can ionization of a drug effect?
Ionization can effect the amount of drug that’s able to bind to an actual receptor
Physical characteristics of drugs
- solid (aspirin)
- liquid (ethanol)
- gas (nitric Oxide)
Nature of drug size
- small (lithium) to large (T-PA)
- b/w 100 and 1000 MW
- related specifically for a receptor and movement within the body
Strength of drug reactivity and bonding in order of strongest to weakest
1) covalent
2) ionic
3) hydrogen
4) dipole induced dipole
5) hydrophobic
Selectivity of drug reactivity and bonding in order of strongest to weakest
1) hydrophobic
2) dipole induced dipole
3) hydrogen
4) ionic
5) covalent
Drug reactivity and bonding of covalent bonds
- Strong bond (tight bond to receptors, making it last longer in the body)
- Irreversible (not very selective; can form with many things)
Drug reactivity and bonding of hydrophobic bonds
- Weak bonds (only last a couple of house)
- Important for lipid interactions (very specific)
What are two details for drug shape?
1) crucial for proper binding (lock and key)
2) chirality (stereoisomerism)
What’s the term for superimposed?
Achiral
What’s the term for something that can’t be superimposed?
Chiral
What is the active form of a drug?
The proper enantiomer; it fits into the receptor to elicit a response
Explain a racemic mixture of a drug
2 equal amounts of s-isomers and r-isomers; only one of them is the active form, so the other half is the part that is responsible for the side-effects of that drug
Examples of ligand gated ion channels
- nicotinic acetylcholine receptors
- glutamate receptors
- GABA receptors
How many subunits are on nicotinic acetylcholine receptors, and what are they?
5 subunits (beta, delta, gamma, and 2 alpha subunits)
How many molecules of acetylcholine have to bind to open the channels?
2 units (1 per alpha subunit)
Where can you find ligand-gated ion channels?
- muscle cell end plates at the neuromuscular junction
- at all autonomic ganglia
- in the CNS
What does prolonged acetylcholine contact with a receptor lead to?
Desensitization of the receptor, making it stay open for long periods of time
Major excitatory neurotransmitter
Glutamate
What kind of receptors are glutamate receptors?
Either ligand-gated ion channels (ionotropic) or G-protein coupled (metabotropic)
Glutamate ionotropic agonists include what?
AMPA, kainite, and N-methyl-D-aspartate (NMDA)
Activation induced depolarization of glutamate receptors leads to what?
Influx of Na+ and Ca2+ and Efflux of K+
What are the main two agonists that cause depolarization of glutamate receptors?
AMPA and kainite
Can NMDA receptors cause depolarization in a glutamate receptor?
They can, but it’s not usually the case because it is plugged up with magnesium. Depolarization unplugs magnesium from the NMDA receptor, allowing calcium to flow through it, allowing it to be even more depolarized
How does depolarization work with non-NMDA receptors?
Glutamate NT is released from pre-synaptic and binds to the non-NMDA receptor, causing sodium to be able to flow through, causing depolarization
Major inhibitory neurotransmitter
GABA receptors
What type of GABA receptor is your ion channel receptor?
GABA-A
What type of GABA receptor is your G-coupled receptor?
GABA-B
Which ion channel receptor is inhibitory?
Which is excitatory?
GABA-A = inhibitory Glutamate = excitatory
What are some things that glutamate is involved in?
Cognitive function and memory
What are some things that GABA-A is involved in?
Anti-anxiety drugs, sleeping agents
How does the GABA-A channel work when a ligand binds to it?
When a ligand binds to it, it opens, causes chlorine to flow into it, causes hyperpolarization, making the cell more negative, inhibiting the likelihood of an action potential to be made (inhibiting action)
What’s the main difference between GABA-A and GABA-B?
GABA-A causes an inflow of chlorine and GABA-B causes an outflow of potassium
What do voltage gated ion channels open in response to?
In response to membrane potential
What are the 3 types of voltage gated ion channels?
Na+ channels
Ca2+ channels
K+ channels
What are voltage gated ion channels not activated by?
Neurotransmitters
Where are voltage gated ion channels located?
In excitable tissues (nerve, cardiac, skeletal muscle)
Explain the role of Gs proteins
Receptor binding activates adenylyl cyclase, which converts ATP to cAMP; cAMP activates protein kinase A
Explain the role of Gi proteins
Receptor binding inhibits adenylyl cyclase, which prevents the conversion of ATP to cAMP, and therefore the activation of protein kinase A
Explain the role of Gq proteins
Receptor binding activates phospholipase C, which releases inositol triphosphate (IP3) and diacylglycerol (DAG) from membrane phosphatidylinositol; IP3 activates Ca2+ and calmodulin-dependent protein kinases; DAG activates protein kinase C
Which two G-protein coupled receptors work on adenylyl cyclase?
Gi and Gs
What are the actions of Gs proteins?
- activates Ca2+ channels
- activates adenylyl cyclase
What are the actions of Gi proteins?
- activates K+ channels
- inhibits adenylyl cyclase
What are the actions of Gq proteins?
-activates phospholipase C
What is a G-protein coupled receptor composed of?
- alpha subunit
- beta subunit
- gamma subunit
When an agonist binds to the G-protein coupled receptor, what exchange happens?
GTP for GDP (GDP is bound to the alpha subunit at rest; when this binding happens, it is switched for GTP)
When the exchange of GTP for GDP occurs in the G-protein coupled receptor binding, what occurs?
The alpha subunit separates from the beta and gamma subunits; the alpha subunit goes over to activate the effector molecule (adenylyl cyclase, calcium channel, or phospholipase C) that already has enzymatic activity built into it; when the ligand is released off of the receptor, there will be exchange of one phosphate to turn back to GDP, causing the receptor to come back together, and goes back to it’s normal resting state
Explain the process of activation of a Gs-coupled receptor
An agonist binds, disassociates the alpha subunit, letting it bind to adenylyl cyclase, which causes ATP to turn into cAMP, activating protein kinase A, which phosphorylates proteins, activating different proteins, leading to a cellular response
Explain the process of Gq-coupled receptor activation
Agonist binds, disassociating the alpha subunit, activating phospholipase C, causing cleavage of PIP2, which creates DAG and IP3; DAG activates protein kinase C; IP3 activates kinases that are calcium and calmodulin dependent; all of this leads to protein phosphorylation and activation or cellular components
Examples of Gs-coupled receptors
Beta adrenergic (B1, B2, B3) Dopamine D1 receptors
Examples of Gi-coupled receptors
Muscarinic M2
Dopamine D2 receptors
Alpha 2 adrenergic
Examples of Gq-coupled receptors
Alpha 1-adrenergic
Muscarinic M3
Muscarinic M1
What ligands activate growth factor receptors of receptor tyrosine kinases?
Insulin Growth factors (EGF, PDGF, HGF)
What ligands activate cytokines receptors?
Growth hormone
Erythropoietin
Interferons
(Examples include: interluken-2 and tumor-necrosis factor)
Explain the difference between tyrosine kinase receptors and cytokines receptors
Tyrosine kinase receptors have built-in intrinsic kinase activity, so it can phosphorylate itself. Substrate/relay proteins bind to the receptor when it is activated (after it’s fully phosphorylated by stealing a phosphate from ATP), which activates those proteins so that they can produce a cellular response
Cytokines receptors do not have intrinsic activity built in, so they recruit the activity through JAK’s, which phosphorylate STAT’s, which leads to a cellular response
Examples of intracellular receptors
Steroid hormones (corticosteroids, mineralocorticoids sex steroids, thyroid hormone, vitamin D) Nitric oxide (produced in endothelial cells
Explain the process of steroid hormones binding to their intracellular receptors
Steroid hormone goes right through the plasma membrane (it’s a lipophilic molecule, so it just passes through), binds to receptor (either in cytoplasm or into the nucleus directly), creating a hormone-receptor complex (acts like subunit of itself) which transcribes mRNA from itself. Then mRNA is transcribed into a new protein.
How does nitric oxide work when it is produced? Where is it produced?
Nitric oxide is produced in the endothelial cells where it readily diffuses across the membrane to react with guanylyl cyclase in order to stimulate cGMP formation and downstream signaling to relax smooth muscle
Examples of second messenger systems
cAMP
cGMP
IP3
DAG
Which receptor has intrinsic kinase activity built into it?
Tyrosine kinase
Which receptor has to have a change in membrane potential to open up the channel?
Voltage-gated ion channel receptors
Which receptor slips right through the plasma membrane and binds intracellularly?
Steroids and nitric oxide (intracellular receptors)
Which receptors have no intrinsic-kinase activity, so they have to recruit it from somewhere else?
JAK-STAT receptors (cytokines receptors)
Which receptor has a ligand bind to it, which opens up the channel?
Ion channel receptors
Which receptor has a ligand bind to it, which disassociates the alpha subunit, which then binds to an effector molecule (adenylyl cyclase, phospholipase C, or calcium channel) in order to cause a response?
GPCR
