Receptors and Cell Signaling Flashcards
Cell Signaling Fast Response
Change in activity or function of enzymes or
proteins in the cell
Cell Signaling Slow Response
Change in amounts of proteins by change in
expression of genes
Acetylcholine - Different responses in different cells
B) heart muscle cells
relax
C) skeletal muscle cell
contract
D) salivary gland cell
secretion of saliva
Ligands
• Can be proteins, small peptides, amino acid derivatives,
hydrophobic molecules (steroid hormones like estrogen)
• Even gases (NO)
• Main categories:
– Small lipophilic molecules: steroid hormones
– Water soluble molecules – hydrophilic – e.g. growth
factors
Lipophillic Ligands
Steroids, Thyroid Horome (Thyroxine), Retinoids
Hydrophillic Ligands
Acetylcholine, proteins, and polypeptides
Steps of G-protein relaying signals
- Ligand binds to receptor
- Conformational change occurs in receptor
• 3. Receptor binds to G protein
GTP bound form is active. — GDP bound is inactive.
• 4. Receptor then acts as a GEF: Guanidine Exchange Factor
• 5. Confirmation of Ga protein is changed such that it kicks out GDP and GTP binds to it
• 6. Ga now becomes active and can bind to
effector molecule and activate effector
molecule
• 7. Effector
GEF
Guanine nucleotide exchange factors
activate monomeric GTPases by stimulating the release of guanosine diphosphate(GDP) to allow binding of guanosine triphosphate (GTP).
cAMP activates this
cAMP dependant Protein Kinase A (PKA)
2 Regulatory subunits and 2 catalytic subunits.
binding of 2 cAMP molecules to regulatory subunits of
tetramer results in release of active C subunits
Cholera Mechanism
• Cholera toxin modifies G protein by
keeping the Ga in the GTP active form
indefinitely
• Leads to 100 fold increase in cAMP
• PKA phosphorylates the CFTR Cl- channel
• Leads to secretion of water
- Water and Cl- come out together
Desensitization: ability to turn off or reject the
signal - Important: cell cycle – cancer
– **Potentiate = turn up
– **Attenuate = turn down
Examples of desensitization
• Remove the signaling molecule:
phosphodiesterases will remove cAMP/cGMP
• Receptor sequestration: endosome
• Receptor destruction: endosomes + lysosomes
(proteases)
GAP Proteins
GTPase-Activating Proteins, or GAPs, or GTPase-Accelerating Proteins are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event.
GRKs
• There are proteins called GRKs: G
protein receptor kinases
• GRKs phosphorylate the receptor
such that another protein called
arrestin will bind to the to the 3rd
intracellular loop and prevents Ga
from interacting with the third loop
• Result is that Ga-GDP does not get
converted to Ga-GTP
Gi(alpha)
Inhibitory Galpha that inhibts AC.
Gqα G-proteins
– Activates PLC
instead of AC
• Phoshoplipase C cleaves
a membrane protein called
PIP2
• Produces IP3 and DAG 2nd
messengers
• IP3: inositol 1,4,5-
triphosphate (diffusible)
• DAG: 1,2-diacylglycerol
(membrane bound)
IP3 triggers release of Ca2+ from endoplasmic reticulum
(calcium storage in ER)
• IP3 does this by binding to an IP3-gated Ca2+ channel +
triggers opening
• Ca2+ released into cytosol so you get increased calcium
concentration
• Ca2+ is a second messenger too!
• IP3 is done.
• Now high cytosolic calcium concentrations
• Both Ca2+ and DAG bind to another protein kinase
called protein kinase C (PKC)
• Conformational change occurs in PKC and it is
activated
• PKC phosphorylates a variety of membrane and
cytoplasmic substrates
Receptor Tyrosine Kinases
- Receptor tyrosine kinases are used for response to growth factors: mediate growth factor signals • Growth factors are proteins released by cells to promote growth of other cells
- Autophosphorylation causes the receptor to act as a scaffold to recruit other proteins to the plasma membrane
- Receptor does not bind to G protein but receptor binds to proteins with domains called the SH2 domains (src homology) – SH2 domain binds to phosphotyrosine
- Src is the first oncogene discovered
In mammals the SH2
Grb2 (adaptor protein)
Receptor Tyrosine Kinase Activity
• Ligand = BOSS
- RTK binds to SH2 domain of Grb2
- SH3 of Grb2 binds to prolines in SOS
• SH3 of Grb2 binds to prolines in SOS (RAS GEF) which then binds to
Ras (small monomeric G protein – small GTPase)
• Ras binds Raf and then things get insane
What is downstream of Ras?
Ras-> (MAP KKK) Raf -> (MAP KK) Mek -> (MAP K) Erk
Insulin signaling
RAS-dependent and RAS-independent signaling via RTK
- *Intermediate scaffold**
- IRS-1
binds GRB-2 or PI3K
GRB-2 -> RAS -> Alterations in gene transcription
PI3K - > PKB -> Alterations in protien and enzyme activity
JAK-STAT Receptors
More direct route for impacting
transcription
- ) receptors bind cytokines and dimerize then get Jaks attached.
- ) Jaks phosphorylate eachother and the receptors.
- ) Receptors bind STATS and then phosphorylate them.
- ) STATS break off and dimerize and go to the nucleus.
Serine-threonine receptors & Smad
More direct route: R-Smad = receptor specific
Smad and forms complex with Co-Smad:
common Smad
- ) Ligand binds to serine threonine receptor
- ) Dimerize and serine is phosphorylated
- ) Type 1 receptory phosphorylates R-SMAD
- ) R-SMAD (phosphorylated) and CO-Samd dimerize and then go to the nucleus.
