(L16) Receptors and Cell Signaling Flashcards
What is endocrine signaling? What are examples? L16 S8
Signal is: -transported via blood stream -long distance -long-lived Examples: -epinephrine
What is paracrine signaling? What are examples? L16 S9
Signal is: -local, diffuses to nearby cells -short-lived Examples: -testosterone
What is autocrine signaling? What are examples? L16 S10
Signal is: -directed secreting cell and neighboring cells of the same type Examples: -chemokines -growth factors in tumors, interlukin 1 (produved by T lymcytes which prote tier own replication udring an immune response)
What is juxtacrine signaling? What are examples? L16 S11
Signal is: -attached to signaling cell and requires direct contact between signaling cell and target cell Examples: -heparin binding epidermal gf (in immune cells)
Also known as direct signaling.
What are the characteristics of hydrophilic signals? L16 S15
- Unable to cross cell membrane
- Receptors on are surface of target cells (GPCR, RTK)
- Use second messengers inside the cell
- Short-lived (seconds to mins)
- signals are small, derived from AA, polypeptides or through lipid metabolism
What are the characteristics of lipophilic signals? L16 S16
- Able to cross cell membrane
- Receptors inside of target cells (cytoplasmic or nuclear)
- molecule-receptor complex acts as transcription factor that acts on DNA or associated proteins
- Long-lived Mostly categorized as hormones
What is the general structure of a GPCR? L16 S19
What is another name for GPCR?
- Extracellular domain (ECD): -binds signal
- Transmembrane domain (TM): -7 α helicies Intracellular domain : will undergo confermational change upon binding of ligand
- (ICD): -interacts with G protein
Another name for GPCR: are 7 TM protein
What is the general GPCR signaling pathway.
- ECD of GPCR binds ligand causing conformation change
- ICD of GPCR exchanges GDP for GTP on G protein, activating it -G protein interacts with membrane bound effector protein generating second messengers
- second messengers interact with target creating biological response
What is the structure of a G protein? What happens to each portion after being activated? L16 S24
Subunits: -α -β -γ
-α subunit has GDP exchanged for GTP upon activation. (when inactive it is bound to GDP)
It also breaks away from the β and γ subunits to interact with effector protein
-ACTIVATION IS A TRANSFER
How can signals be desensitized? L16 S25
- drop in hormone levels
- remove secondary signaling molecule (phosphodiesterase will remove camp/cgmp)
- sequester receptor (forms endosomes that later refuses with cell membrane)
- destroy receptor (forms endosomes that fuses with lysosome, only happens if the receptor is damaged)
What are the different secondary effector methods of GPCR signaling? L16 S28
Gs: -ligand activates makes alpha GTP
- alpha subunit activates adenylate cyclase producing cAMP
- cAMP activated PKA -cAMP removed by phosphodiesterase
Gi:
- ligand activates
- alpha subunit inhibits adenylayte cyclase
- cAMP is not produced and PKA is not activated
Gt: -light activates makeing alpha GTP
- alpha GTP activates cGMP
- cGMP phosphodiesterase removing cGMP
Gq:
- ligand activates
- activates PLC cleaving PIP into IP3 (activates Ca+ signaling) and DAG (activates PKC)
What is the effect of hydrolyzing cyclic nucleotides and what happens when this process is inhibited? L16 S30 Panini pg. 100
Cyclic nucleotides act as secondary messengers so hydrolyzing them stops their downstream biological activity. When hydrolysis is inhibited, the secondary messenger increase in concentration and increase the downstream biological effect.
What is the effect of cholera toxin? L16 S31 Panini pg. 100
Overly activates Gsα by decreasing its GTPase activity preventing it from being inactivated. Stimulates adenylate cyclase.. This is because ADP is riboslyated in the Gsalpha ARG.
-over abundance of camp causes intestinal cells to open Cl- channels, causes a loss of eletrolytes and water which causes diarrhea
What is the effect of pretussis toxin? L16 S33
Inhibits Giα preventing inhibition of adenylate cyclase because of ribosylation of Cys on Gia
- less inhibiton of AC and hense over production of camp
- in airway epithelial cells pertussis, toxin causes loss of fluids and excesive mucous secretion which presents as whooping cough
What is the effect of NO? L16 S34
- NO is produced in epitelial cells by arginine and is repsonsible for smooth muscle relaxation
- it diffuses into nehiboring muscles and activates guanylate cyclase which makes cGMP –> resluts in vasodilation and smooth muscle relaxation
- NTG AND OTHER nitrates decompose to form NO and help to lower BP
- patients that take nitrates should not drugs that inhibit cGMP which can cause extreme vasodilation and fatal drops in BP
What is the general structure of RTKs? L16 S37
Extracellular domain: -ligand binding site
Transmembrane domain: -single helix
Intracellular domain: -possesses tyrosine kinase activity
What is the general mechanism of RTK signaling? L16 S38
-binding of ligand causes dimerization -tyrosine residues are phosphorylated and recognized by other molecules such as adaptor and docking protiens (such as SH2 domain of Grb2)
Ras-dependent pathway: -MAPK activated
Ras-independent pathway: -other kinases activated
A ligand - receptor complex
activates or inhibits cellular pathways
What is an effector?
Alters the activity of different compontents down stream and generates secondary messengers
Name the 2 DNA binding transcritpion factors
- cytoplasmic recetpors: binds to specific DNA sequence called hormone response elment (HRE) in the promoter region of specific genes
- nuclear recetpors: already present in nucleus and bound bound to DNA
How to GPCR return to its inactive state?
- The intrinsic GTPase activity of the G protein hydrolyzes its bound GTP to GDP and phosphate Pi
- This action is accelerated by GTPase activating protein (gap)
Epi and beta adrenergic recetptor
Gs
Histamine
Gs
Epi/norepi
alpha adrenergic receptor: Gi
Dopamine and Dopaine receptor
Gi
Acetylcholine
Gq
Light
Gt
cGMP phosphodiesterase does what? What actions do the hibitors do?
- Hydrolyes cGMP to 5’ GMP
- Inhibitors of CGMP PE increase concetration of cellular cGMP and prolong effects for a greater amount of time leading to smooth muscle relaxtion, vasiodilation and errection: ciagra, levitra and cialis
Caffine ihibits
PDE
Antihistamines do what?
- inhibit G protein coupled receptors singaling
- histamine is a ligand that binds to four histamine GPCRs
- antihistamines are lipholic compounds that block the effect of histamine to H1 GPCRs
- made from histidine
- ex are zertyc, claritin, diahenhydrmine, bendadryl
How are RTK singals terminated
- degration of ligand by extracellular proteases
- ligand induced endocytosis of receptor
- ras inactivation
- dephos of proteins targets by phosphatases
GRB2 / IRS 1
Adaptor protien that binds to RAS
RAS dependent singaling facilitated by _________.
Mitogen activated protein kinase family
Ras indepenendent singaling facilitated by
different kinases
Momeric G protiens
- part or RAS superfamily of small g proteins which play a role in transdction of singlas from memrbane receptor to effector proteins: kinases
- use GEF proteins which helps exchange a GDP to GTP
- have intrinisc GTPase activity: mutations lead to cancer
_____ of lung and colon and ___ or pancreating cancers associated with activiting point mutations in ras.
30-50
90
Excessive singaling from mutated/ overexpressed RTKs associated with ____.
Inhibitors of RTK is what?
cancer
-HER2 belongs to family of EGF binding RTKs
