Receptors and signalling Flashcards
what is endocrine signalling?
signal (hormone) is transported via blood
Ex: epinephrine is released by adrenal medulla to go to heart
“Long lasting
what is paracrine signalling?
Signal (paracrine factor) diffuses to
neighboring cell of a different type
Ex: testosterone made in Leydig cells induce spermatogenesis in Sertoli & germ cells
“Short-lived” signal
what is autocrine signalling?
secreting cells express surface receptors
for the signal. Same cell - uses receptors on own
surface
Ex: interleukin-1
what is juxtacrine signalling?
signal binds to signaling cell which then
binds to receptor on adjacent target cell.
Ex: heparin-binding epidermal growth factor
Binding to EGF receptor
Immune cells
what do lipophilic signals do and what is their significance?
Able to pass through plasma membrane
Binds to specific intracellular receptor proteins in cytosol or nucleus
several families of DNA binding transcription factors
long half lives
what are the two types of receptors that lipophilic signals target?
nuclear receptors
cytoplasmic receptors
both regulate transcription of genes
what do hydrophilic signals do and what is their significance?
Cannot penetrate PM
Interacts with specific receptors at cell surface
Signaling molecule-receptor complex starts production of second messenger molecules inside cell
short lived
GPCRs and RTKs
what are the three binding domains of GPCR?
- extracellular Domain (ECD)- binds to signal
- Transmembrane Domain (TM)- composed of 7 A-helices
- Intracellular Domain (ICD)- interacts with G protein
how do GPCRs G activate proteins?
signaling exchange of GDP for GTP leading to second messenger activation
how does GPCR activation process work?
Ligand binds to receptor,
conformational change in receptor,
GPCR interacts with G proteins,
receptor acts as GEF, GDP into GTP
Ga changes and kicks out GTP for GDP,
Ga binds to and activates or inactivates effector molecule, secondary molecules
what subunits are a part of the trimeric g protein?
Alpha, Beta, Gamma
Inactive G protein has GDP bound to A-subunit
alpha bound to beta and gamma
What is the Gs pathway, what does it do?
stimulates adenylate cyclase,cAMP -> PKA (on) -> phosphorylation of downstream targets
What does Epi do to Gs
relaxes bronchial & smooth muscle of intestine
What does Histamine do to Gs?
bronchoconstriction, allergic
What is Gi?
inhibits adenylate cyclase
Adenylate cyclase (off)
what does Epi do to Gi?
constriction of smooth muscle
What does dopamine do to gi?
increase HR
what does gt do?
cGMP phosphodiesterase
If bound by light (vision)
what does Gq do?
activates Phospholipase C (PLC)
DAG + IP3 -> CA2+ release from ER/SR -> Calmodulin complex
What if acetylcholine binds to Gq?
bronchoconstriction and stimulation of salivary glands; parasympathetic NS
Whats the significance of cholera and GPCR?
stops inactivation of Gs-A
ADP ribosylation of Arg, decreases GTPase activity
Gs-A stays ON causing overproduction of cAMP
cAMP abundance in GI cells open Cl- channels
Loss of water, and electrolytes due to diarrhea
Pertussis Toxin and GPCR?
blocks activation of Gi-A
Blocks Gi-A from turning off Adenylate cyclase
ADP ribosylation of Cys on Gi-A prevents activation and dissociation of A-subunit
Less inhibition of AC and Overproduction of cAMP
Loss of fluids and excessive mucus in airway epithelial cells
what is signaling desensitization?how is it done?
Ability to turn off or “ignore” a signal
Decreased hormone levels -> decreased adenylyl cyclase activity -> decreased cAMP -> decrease PKA activity
Removing signaling molecule: phosphodiesterase removes cAMP/cGMP
Receptor sequestration: endosome
Receptor destruction
Hydrolysis of cyclic nucleotides, significance?
enzymes hydrolyze cyclic nucleotides to regulate cellular levels
cAMP phosphodiesterase: hydrolyzes cAMP to AMP
cGMP phosphodiesterase: hydrolyzes cGMP to 5’-GMP
Inhibitors of cGMP PDE increases concentration of cGMP leading to smooth muscle relaxation and vasodilation
what is the significance of Nitric oxide and smooth muscle relaxation?
responsible for relaxation of smooth muscles.
NO diffuses to neighboring muscles and activates guanylate cyclase -> productions of cGMP
lower blood pressure
Pts taking nitrates should NOT take drugs that inhibit cGMP PDE (ie viagra)
extreme drops in BP
Antihistamine and G protein-coupled receptor signaling?
Block binding of histamine to histamine receptor
Are lipophilic compounds
signaling via receptor tyrosine kinases (RTK)
ECD contains binding site
Single helix spans membrane
ICD possesses Tyrosine Kinase Activity
Monomeric G proteins, how do they work? steps in the process?
- Upon ligand binding to RTK, ECD dimerizes
- Specific tyrosine are autophosphorylated
- Phosphotyrosine binds to adapter and docking proteins (SH2 & Grb2)
- Activates downstream signaling pathway RAS dependent or independent
- Triggers phosphorylation of protein targets in nucleus, PM and cytoplasm -> alteration in gene transcription and protein activity
- RTK signaling is terminated
RTKs and cancer , significance?
Target of pharmacological inhibitors due to excessive signaling from mutated/overexpressed RTKs associated with cancer
Breast cancer drug herceptin targets HER2, which belongs to EGF-binding RTKs
Ras and cancer, significance?
Mutant forms of RAS, or its GEFs or GAPs have been used in human cancers
30-50% lung and colon cancer / 90% pancreatic cancers associated with activating point mutations in Ras
Mutations decrease GTPase activity and keep it active
Insulin signalling via RTK, explain it?
Insulin activates RTK creating an intermediate scaffold including IRS-1
Binds to either GRB-2 (RAS-dependent) or PI3-Kinase (RAS-independent)
What is the Ras independent pathway?
Alters protein and enzyme pathway to plasma membrane
Ex: activation of glycogen synthase
What is the Ras dependent pathway?
Alters gene transcription:
Ex: Increased transcription of glucokinase
