Biosignaling Flashcards
Do receptors and ligands form covalent or non-covalent bonds?
Non-covalent
What are tissue-specific receptors? Give an example.
- Receptors are only present in one or two tissues
- TRH receptor in pituitary cells
What are tissue-specific receptor targets?
- Receptors are present in various tissues, but they respond differently in different cells
- Adrenalin receptor in the liver increases glycogenolysis and in adipocytes stimulates fatty acid release
What is a receptor?
Membrane-bound or soluble protein or protein complex, which exerts a physiological intrinsic effect after binding its natural ligand
What term applies to a situation in which both hormones are bound to receptors on the same cell?
Integration
What is signal amplification?
When enzymes activate enzymes, the number of affected molecules increases geometrically in an enzyme cascade
What is desensitization/adaptation?
- Receptor decreases its response to a signalling molecule when that agonist is in high concentration
- Cascadal mediators inhibit the ligand and receptor; stops the response
Give examples of desensitization.
- Smell
- Bright light to dark light
- Skin sensation
What is integration?
Two different receptors for two different signals modulate for the same response
What does the response of signal integration depend on?
- Depends on many receptor-ligand interactions
- Cells respond to all of them as a whole
Give examples of some signals to which cells respond.
- Antigens
- Growth factors
- Hormones
- Light
- Neurotransmitters
- Nutrients
- Odorants
What are the two ways a ligand-receptor can induce a response?
- Ligand-receptor directly induces a response
- Ligand-receptor –> activity of effectors –> response (indirect)
How many GPCR receptors are there?
We don’t know; could be 800 could be more
Which receptor does 50% of drugs target? Give an example.
- GPCR
- Prozac
What is the ligand and the receptor in the cAMP GPCR example?
- Ligand: epinephrine
- B-adrenergic receptor
What is Gs? What does it increase/decrease?
- Stimulates adenylyl cyclase
- Increases levels of cAMP in the cell
What is Gi? What does it increase/decrease?
- Inhibits adenylyl cyclase
- Decreases levels of cAMP in the cell
What is Gq? What does it increase/decrease?
- Activates phospholipase C (PLC)
- Increases calcium levels in the cell
In the cAMP mechanism of a GCPR receptor, what does the Gsa subunit move towards after it dissociates frmo Gsbg?
Moves towards adenylyl cyclase
What is the role of adenylyl cyclase in the cAMP mechanism of GCPR?
Catalyzes the formation of cAMP from ATP
In the cAMP mechanism of a GCPR receptor, what does cAMP do?
Activates PKA
What causes the cellular response to epinephrine in the cAMP mechanism of a GCPR receptor?
Phosphorylation of cellular proteins by PKA
How does adenylyl cyclase catalyze the formation of cAMP from ATP?
Removes two phosphate groups from ATP
What does AKAP stand for? What is its role? In which mechanism is it located?
- a-kinase anchoring protein
- Anchors PKA
- In the cAMP mechanism of a GCPR receptor
What is the structure of the PKA/AKAP complex?
- AKAP anchors 2 PKA subunits (dimer)
- Each PKA subunit has a catalytic subunit and a regulatory subunit
Which subunit does cAMP bind to in the PKA complex?
cAMP binds to the regulatory subunit
How many cAMPs are required to activate a dimer of PKA?
4 molecules of cAMP for 2 molecules of PKA
How does PKA phosphorylate other proteins?
When cAMP binds to the regulatory subunit, the catalytic subunit is released and the substrate-binding cleft is now activated; it can phosphorylate other proteins
Give examples of popular GPCRs.
- Ghrelin receptor
- Gonado trophin receptor
- Histamine H1 receptor
If epinephrine binds to a receptor in the liver cell, how many molecules of glucose are generated?
If epinephrine = x, glucose = 10 000x
What are the two ways the signal of the cAMP mechanism in a GCPR receptor can be terminated?
1) Conversion of cAMP to AMP by cyclic nucleotide phosphodiesterase; since AMP is not functional and cannot activate PKA
2) Modulators of GTPase activity
What converts cAMP to AMP?
Cyclic nucleotide
What are the modulators of GTPase activity? (2)
- GAP (GTPase activator protein)
- RGS (Regulators of the G-Protein)
Give two examples of signals that use cAMP as second messengers. Are they Gs or Gi?
- Epinephrine: Gs
- Prostaglandins: Gi
In the IP3 and Ca mechanism in a GPCR, is Gs or Gi used?
Neither, Gq is used
What does the activated Gq with GTP move towards in the IP3 and Ca mechanism in a GPCR?
Moves towards PLC
What does PLC mean?
Phospholipase C
What is the role of PLC? Which mechanism is it implicated in?
- Cleaves PIP2 to IP3 and diacylglycerol
- In the IP3 and Ca mechanism in a GPCR
What is the role of IP3? Which mechanism is it implicated in?
- Binds to a specific receptor-gated Ca2+ channel, releasing sequestered Ca2+
- In the IP3 and Ca mechanism in a GPCR
What activates protein kinase C? Which mechanism is it implicated in?
- Diacylglycerol and Ca2+
- In the IP3 and Ca mechanism in a GPCR
Give examples of signals that act through PLC, IP3 and Ca2+.
- Angiotensin
- Glutamate
- Oxytocin
What are the three pathways of tyrosine kinase receptors?
- MAPK
- PIP3
- JAK-STAT
What is the ligand and the receptor in the MAPK pathway example?
Ligand: Insulin
Receptor: Insulin receptor
Where does the MAPK pathway take place?
In the cellular membrane at first, then ERK moves into the nucleus to phosphorylate transcription factors
What is PI-3K’s role? Which mechanism is it implicated in?
- Converts PIP2 to PIP3
- PIP3 (RTK)
What binds to PIP3? How is it phosphorylated? Which mechanism is it implicated in?
- PKB bound to PIP3
- PDK1 phosphorylates PKB
- PIP3 (RTK)
What is PKB’s role? Which mechanism is it implicated in?
- Phosphorylates GSK3 on a serine residue
- PIP3 (RTK)
What is GSK3’s role when it is active? What does it prevent when its inactive? Which mechanism is it implicated in?
- Convert glycogen synthase (GS) to its inactive form by phosphorylation
- When GSK3 is inactive, GS remains active and the synthesis of glycogen from glucose is accelerated
How is the uptake of glucose increased in the PIP3 mechanism?
PKB stimulates movement of glucose transporter GLU4 from internal membrane vesicles to the plasma membrane
What does GS mean?
Glycogen synthase
What does MAPK mean? Why?
Mitogen activated protein kinase (simulates mitosis)
What does JAK mean?
Janus Kinase
What does STAT mean?
Signal Transducer and Activator of Transcription
Why can dimerized STAT travel into the nucleus? Which mechanism is it implicated in?
- Because the dimerization exposes NLS which allows it to travel into the nucleus
- JAK pathway
Which pathway can the JAK mechanism induce?
The MAPK cascade to alter gene expression
What is ANF? When is it secreted?
- Atrial natriuretic factor
- Hormone secreted by the heart when it is stretched (when the blood volume is high)
What signals are implicated when the blood volume is high?
- ANF (stretched heart)
- Kidney (guanylyl cyclase)
- Na excretion (draws water out)
- Reduced blood volume
Which ligand and which receptor are used in the guanylyl cyclase example?
Ligand: ANF
Receptor: ANF receptor
How does the receptor guanylyl cyclase work?
- Guanylyl cyclase converts GTP to cGMP
- Activates PKG
Why are there soluble guanylyl cyclases?
Soluble since they are in the cytoplasm, not the cell membrane
What do soluble guanylyl cyclase proteins all have? What is one of their ligands?
- All have Heme
- Citric oxide (NO)
How is the signal terminated in a guanylyl cyclase receptor?
cGMP is converted to 5’-GMP by a phosphodiesterase, which terminates the signal
What kind of cells are excitable? What processes are controlled by these excitable cells?
- Neurons: neuron signals
- Muscles: muscle contraction
Ion channels are “gated”. What can they be stimulated by?
- Ligands (ligand-gated)
- Changes in membrane potential (voltage-gated)
What compounds do ion channels allow?
Anions or cations
Which compounds maintain the membrane in a polarized state?
- Na+
- K+
- ATPase
What is the resting membrane potential?
-70 to -50 mV
What is the normal state of the membrane potential?
Polarized
How are the outside and the inside of the plasma membrane in the normal state of the membrane potential?
Outside: +
Inside: -
What causes a depolarized membrane potential status?
- Inside is less negative
- Above -50mV
What causes a hyperpolarized membrane potential status?
- Inside is more negative
- Below -70mV
How does Na+ travel?
Outside (high) to inside (low)
High to low
How does K+ travel?
Inside (high) to outside (low)
High to low
How does Ca2+ travel?
Outside (high) to inside (low)
High to low
How does Cl- travel?
Inside (LOW) to outside (HIGH)
LOW TO HIGH
Which ion travels from low potential to high potential?
Cl-
What is a cation? What is an anion?
Cation: +
Anion: -
What happens when a neuron is excited?
Depolarization stimulates ion channels
Which ion helps vesicles open and release their neurotransmitter across the synaptic cleft?
Ca2+
How do Na+ and Ca2+ go into the cell and depolarize the next neuron?
Neurotransmitters activate the ligand-gated ion channel
In a voltage gated ion channel, what senses a change in potential?
Voltage sensor
In a voltage gated ion channel, what does the selectivity filter do?
Decides what type of ion can go in
What allows for the opening of a ligand-gated channel? What influx is allowed in?
When ligand binds, it causes a conformational change, which allows for the influx of ions
Which receptors allow the influx of cations?
- Acetylcholine
- Serotonin
- Glutamate
Which receptors allow for the influx of anions?
Glycine
What is the integrin recognition sequence? What does it mean?
- Arg-Gly-Asp
- Extracellular matrix proteins need Arg-Gly-Asp in order for integrins to recognize
In which direction is signal transduction?
Bidirectional (inside to outside, or outside to inside)
What are integrins?
Integrins are proteins that function mechanically, by attaching the cell cytoskeleton to the extracellular matrix, and biochemically, by sensing whether adhesion has occurred.
What are integrins connected to on the inside?
Actin filaments in the cytoskeleton
What are integrins connected to on the outside?
Fibronectin in extracellular matrix
What two compounds connect integrins to the cytoskeleton? What are their roles?
- Vinculin and talin
- Can help with cell motility, interact with extracellular matrix (changes shape and movement)
- Talin and vinculin have been targets as cancer therapy
How many different nuclear receptors are encoded in our genome?
48-50
Nuclear receptors are for what kind of hormones? Why?
- Fat-soluble
- They can diffuse through the cell membrane
Where are most nuclear receptors? Where are some?
- Most: cytoplasm
- Some: nucleus
Give examples of hormones that can bind to nuclear receptors.
Steroid, thyroid, retinoic acid, vitamin D
Where does the dimerization of nuclear receptors occur?
In the nucleus OR the cytoplasm
For each class of steroid nuclear receptors, what % of them can be localized in the plasma membrane?
5-10%
How do nuclear receptors located in the cytoplasm regulate gene expression?
Once dimerization occurs in the cytoplasm, it will MOVE to the nucleus
Protein phosphorylation by a kinase occurs on 3 types of amino acids. What are they?
- Serine
- Threonine
- Tyrosine
