Receptors & Cell Signaling Flashcards
Types of Signaling
1) Endocrine
2) Paracrine
3) Autocrine
4) Juxtacrine
Cell signaling steps
1) Lipid/water soluble molecule (ligand) secreted in response to stimulus
2) Ligand binds to target cell protein receptor
3) Ligand-receptor complex activates or inhibits something
4) Dowstream effects occur, amplified by secondary messengers
5) Signal stops via ligand dissociation or inhibition
Endocrine signaling
- Transported via blood
- Long distance signaling
- Example: Epinephrine, released by adrenal medulla and acts on heart
- Long lasting
Paracrine
- Signal diffuses to neighboring cell
- Example: Testosterone
1) Leydig cells secrete/synthesize - Short-lived signal
Autocrine
- Signal acts on cell that released it
- Example: Interleukins
1) T cells secrete interleukin which promotes T cells to replicate during an immune response
Direct/Juxtacrine
- Requires cell to cell contact
- Signal binds to signalling cell, which then binds to target cell receptor
- Example: HB-EGF
1) In immune cells
Hydrophilic signaling (and receptors)
-Can’t cross membrane, bind to receptors (epinephrine, insulin)
Receptors –> signal cascade via SECOND MESSENGERS (small, short-lived)
-Downstream response triggered
Receptors: G-protein-coupled receptors (GPCR), Receptor tyrosine kinases (RTKs)
Lipophilic signaling
- Diffuse through membranes (steroids, thyroid hormones)
- Signal binds to receptors in the cell (cytosol, nucleus) -> formed complex acts as transcription factor
- Long lives (hours to days)
Cytoplasmic receptors
- Heat-shock protein (HSP) dissociates when hormone-receptor complex (HRC) is formed
- HRC moves to nucleus —> initiates gene transcription via hormone response element (HRE)
Nuclear receptors
- Already in nucleus, bound to DNA
- Signal hormone activates complex for interactions with proteins for gene transcription
G-Protein Coupled Receptor structure (Important ion what clinical context)
Extracellular domain (ECD), Trans Membrane Domain (TM), Intracellular Domain (CD)
-TARGET FOR DRUG THERAPY!!!
Steps of a G-Protein Signal Relay
1) Ligand binds to GCPR, incurring conformational change
2) GCPR binds to G-protein, acts as GEF (Guanidine Exchange Factor), GDP exchanged for GTP, activating G-protein
3) G-protein activates effector protein, which triggers cascade of secondary molecules
Signal Desensitization Mechanisms
1) Hormone level drop
- Decreased cAMP and PKA activity
2) Removal of the signal molecule
3) Receptor isolation by endosome
4) Receptor destruction (endosome + lysosome + proteases)
Receptor recycling
-Depends on quality of the receptor — good quality = fast or slow re-insertion to membrane. Poor quality results in enzyme degradation
Types of GCPR Signaling
1) Gs — Adenylate cyclase (stimulates)
2) Gi — Adenylate cyclase (inhibits)
3) Gt — cGMP Phosphodiesterase (stimulates)
4) Gq — Phospholipase C (activates)
Gs signaling steps
1) GPCR activated by ligand, which activates Gs-alpha via GTP -> GDP.
2) Gt-alpha activate Adenylate Cyclase via ATP
3) cAMP is activate by AC, which then activate PKA to target proteins
4) Phosphodiesterase (PDE) inactivates cAMP
Gi signaling steps
1) GCPR is activated by ligand, which activates Gi-alpha.
2) Gi-alpha does not activate AC
Gt signaling steps
1) GPCR activated by ligand, which activates Gt -alpha via GTP -> GDP.
2) Gt-alpha activate cGMP PDE via cGMP
KEY: how vision occurs…..Rhodopsin has cGMP PDE
Gq signaling steps
1) GPCR activated by ligand, which activates Gq-alpha via GTP -> GDP.
2) Gq-alpha activates Phospholipase C
3) PLC release PIP, which combines with DAG to activate Protein Kinase C (PKC) -> phosphorylation of target proteins
4) IP3 breaks from PIP to release Ca2+ from Endoplasmic Reticulum, which activates Ca2+ calmodulin=dependent proteins
Name the GCPR proteins for:
1) Epinephrine
2) Histamine
3) Epinephrine/norepinephrine
4) Dopamine
5) Acetylcholine
6) Light
1) Gs
2) Gs
3) Gi
4) Gi
5) Gq (q sounds like -choline)
6) Gt (Gt, more like G-see…light!!)
Effect of cGMP PDE inhibition on cells
- Since CGMP PDE turns cGMP into 5’-GMP, cellular concentration of cGMP are increased, leading to smooth muscle relaxation and vasodilation (i.e. Viagra)
- Caffeine does the same and increases heart rate
- NITRIC OXIDE IS BAAAADDDDDD = Low BP
How does Cholera toxin affect the body?
- Prevents activation of Gs-alpha
- AC continuously stimulated -> overproduction of cGMP
- Cl- channel opens in intestine via CTFR (cystic fibrosis) = loss of electrolytes and water in diarrhea
How does Pertussin toxin affect the body?
- Prevents Gi activation by preventing dissociation of Gi-alpha from G-protein complex
- Prevents Gi from inhibiting AC
- cAMP build up —> loss of fluids and excessive mucus = Whooping cough
What do antihistamines do?
Inhibit GCPR signaling by blocking effects of histamine to the H1 GCPR
What is the structure of Receptor Tyrosine Kinase (RTK)?
- Integral protein
- ICD possesses TYROSINE KINASE ACTIVITY
RTK Signaling steps
1) Ligand bind to RTK on the ECD
2) Kinase activated, tyrosine residues are phosphorylated
3) Docking proteins recognized phosphotyrosines and attach (dock)
4) Cascade activated to trigger protein, gene transcription activity via RAS-dependent or RAS-independent
5) Signal terminated
What mediates RAS-dependent signaling
-MAPKinase family of enzymes
RAS relevance to cancer
- Mutations with RAS gene cause cancer, as well as GTPase activity, causing it to REMAIN ACTIVE
- Involved in a wide variety of human cancers
- Target of drug Therapy (breast cancer drug Herceptin targets HER2, a binding protein for RTK
Explain the importance of Small G proteins
- More than 150 in RAS family
- Importance in signal transduction from membrane receptors to effector proteins - Cell proliferation, survival, membrane rand transport
- Because they have intrinsic GTPase activity, MUTATIONS OFTEN LEAD TO CANCER
