Receptors And Cell Signaling Flashcards
What are the two types of signals?
Water soluble
-hydrophilic
Lipid soluble
-hydrophobic
Epinephrine, insulin, and glucagon are examples of what time of signaling that initiates production of a second messenger, and has a shorter half life
Hydrophilic signaling
What are two receptors involved in hydrophilic signaling
G-protein couple receptors and receptor tyrosine kinase
Steroid hormones, thyroid hormones, and retinoids are examples of what type of signaling that binds to receptors proteins inside the cell and create a transcription factor from the molecule-receptor complex
Lipophlic signaling (hydrophobic)
Where can lipophilic signaling receptors be located
Cytosol or nucleus
_____ exist in an inactive complex with HSP90. Upon binding of signal, the HSP dissociates and the receptor complex translocates to the nucleus where it binds to a specific DNA sequence called the HORMONE RESPONSE ELEMENT in the promoter region
Cytoplasmic receptors
(Hydrophobic signaling)
*regulates transcription of genes
_____ receptors are already present in the nucleus and are bound to DNA awaiting for a signal to be activated
Nuclear receptors
-hydrophobic signaling
-regulates transcription of genes
Explain the structural motifs of G-Protein coupled receptors (GPCRs or 7TM receptors)
**heterotrimeric / hydrophilic
- extra cellular domain-binds to signal
- Transmembrane domain-composed of 7 alpha helixes
- Intracellular domain-interacts with G proteins
The intracellular domain of a GPCR activates the G protein by triggering what
Exchange of GDP—> GTP
An activated GTP-bound G protein interacts with a membrane-bound _________, usually producing a second messenger
Effector protein/ effector enzyme
Where is the GDP bound in inactive G proteins
To the alpha subunit which is attached To the beta and gamma subunits of the trimeric protein (has alpha, beta, and game subunits)
The activation of G proteins by exchange of GDP to GTP occurs via the action of _____
GEF
Guanine nucleotide exchange factor
*The GTP binds to the alpha subunit that then dissoates from the beta and gamma subunit of the trimeric protein
What is the function of intrinsic GTPase activity in G proteins? And what can accelerate its function?
Intrinsic GTPase activity returns the G protein to its inactive state by hydrolyzing the GTP to GDP
It can be accelerated by GTPase-activating protein (GAP)
7 simple steps of a G protein signal relay
- (Hydrophilic signal) ligand binds to GPCR
- Conformational change to GPCR
- GPCR able to interact and bind with the G protein inside of the cell
- Receptor than acts as a GEF and exchanges GDP for GTP
- Alpha subunit dissociates form other subunits
- Activated alpha subunit binds to activate or inhibit effector protein
- Effector molecule catalyzes reactions that produce secondary messengers, GTP hydrolyzes
Explain GPCR signaling via Gs pathway
- The activated GTP-bound alpha subunit activate adenylate cyclase (AC)
- AC converts ATP —> cAMP
- CAMP activates PKA
- PKA phosphorylates Target proteins and alters activity
Explain GPCR signaling via GI pathway
- Activated GTP-bound alpha subunit inhibits adenylate cyclase (AC) activity
- Inhibition of AC results in no cAMP production or activation of PKA
Explain GPCR signaling via the Gt pathway
- The primary signal comes from light (the g -protein is rhodopsin)
- Activated GTP-bound alpha subunit activates cGMP phosphodiesterase
- CGMP PDE converts cGMP—> 5’-GMP
- Important for vision
Explain the GPCR signaling pathway via Gq pathway
- Activated GTP-bound alpha subunit activates PLC which makes PIP
- PIP goes on to make DAG and IP3
- IP3 activates a calcium channel that release calcium from the ER/SR
- Release Ca2+ activates the Ca2+calmodulin-complex which then activates calmodulin dependent proteins
- DAG activates PKC which phosphorylates target proteins and alters activity
Epinephrine and histamine utilizes which specific GPCR pathway
Gs
Epinephrine/ norepinephrine and dopamine utilize what GPCR specific pathway
GI
Acetylcholine uses what GPCR specific pathway
Gq
Light signals use what GPCR specific pathway
Gt
What hormone can be administered to relieve bronchospasms during an asthma attack or to restore cardiac rhythms after cardiac arrest
Epinephrine
Which can follow a Gs or GI pathway
What is the function of cAMP phosphodiesterase
And cGMP phosphodiesterase
Hydrolyze cAMP -> AMP
Or hydrolyze cGMP -> 5’-GMP
What happens when cGMP PDE and cAMP PDE is inhibited
CGMP-PDE inhibition (by viagra) increases cGMP levels which causes smooth muscle relaxation and vasodilation
CAMP-PDE inhibition (by caffeine) leads to increased heart rate
What is produced by epithelial cells to promote relaxation of smooth muscle and vasodilation by producing cGMP
Nitric oxide (NO)
- there some patients take nitrates to lower blood pressure
- patients should not take nitrates and cGMP PDE inhibitors at same time bc it can cause fatal drops in BP
What does Cholera toxin do to G-protein signaling
-prevents inactivation of Gs
-from covalent modification of alpha subunits ADP ribosylation of Arginine which decreased GTPase activity
(Resulting in over production of cAMP which causes intestinal cells to open Cl- channels which causes loss of water and diarrhea)
*contaminated water
What does Pertussis (whopping cough) do to g- proteins
-prevents Gi activation
(Resulting in overproduction of cAMP causing loss of fluid and excessive mucous in airways)
-ADP ribosylation of cystine causes dissociation of alpha subunit
What is the function of G-Protein Receptor Kinases (GRKs)
GRK’s phosphorylates GPCR’s
This causes:
- Arrestin to bind to the 3rd loop of the phosphorylated GPCR
- Alpha subunit can not bind to 3rd loop now
- Results in inability to convert GDP to GTP there for inactive complex
**impairs downstream reactions of GPCRS
Describe the structural motif of Receptor Tyrosine Kinase (RTK)
- extracellular domain binding site (signals tend to be growth factors)
- single alpha-helical transmembrane domain monomeric)
- intracellular domain holds tyrosine kinase activity
The binding of a Ligan to RTK extracellular domain causes what
Dimerization (which triggers TK activity )
-dimerized receptors phosphorylate tyrosine residues
Phospho-tyrosines recognized by adaptor and docking proteins (SH2 domain of Grb2) activate downstream signaling pathways of _____
RAS-dependent (MAPK pathway)
And
RAS-independent (other kinase pathway)
*both trigger phosphorylation of specfic protein targets which affect transcription and activity of genes
Adaptor proteins GRB-2 and IRS-1 have domains called ___ and ____ which recognize and bind to motifs receptors with phosphorlayted tyrosines
SH2 and PTB
T/F
RTK’s need additional GEF’s to come in to convert GDP to GTP
True because it is monomeric
RAS-dependent signaling is facilitated by what
Mitogen-activated protein kinase (MAPK)
Insulin signaling via RTK
IRS-1 binds to GRB-2 (RAS-DEP) or P13-kinase (RAS-INDP)
RAS DEP:
- alters gene transcription
- increases glucokinase
RAS INDP:
- alters protein/enzyme
- increases GLUT4 movement
