What are ACE-inhibitors? How do they work?
1) drug that controls blood pressure
2) blocks angiotensin converting enzyme (ACE) from converting angiotensin I into angiotensin II
What are the 3 modes of actions for chemical messengers?
1) endocrine (thru blood)
2) paracrine (adjacent cell)
3) autocrine (same cell)
What are the 3 types of plasma membrane receptors?
- ion channel receptor
- receptor kinases
- heptahelical receptors
What are the 5 classes of chemical messengers, and what are their functions?
- neuropeptides: nervous sys
- hormones: endocrine sys
- cytokines: immune sys
- eicosanoids: injury
- growth factors: cell proliferation
Define second messengers.
non-protein molecules that amplify cell signal, have ability to diffuse, and have a fast response relative to proteins that turn genes on
What is the sequence of cell signaling steps?
chemical messenger --> cell receptor --> signal transducer proteins --> second messengers --> effector activation --> termination of signal
Describe the intracellular signaling pathway. Example?
lipophilic chemical messenger --> diffuses across PM --> binds to receptor in cell --> increased gene transcription; ex. cortisol
What are the 3 types of second messengers?
1) phosphatidylinositol (PIP) signaling 2) cAMP 3) Ca2+
What do kinases & phosphatases do?
1) kinase: phosphorylate 2) phosphatase: remove phosphate
Describe the ion channel receptor pathway. Example?
1) chemical messenger binds to PM receptor --> channel opens, allowing Na+ ions to flow into cell 2) nicotinic acetylcholine receptor
Describe the INF or IL/JAK/STAT kinase signaling pathway.
cytokine binds receptor --> JAKs dimerize & cross-phorylate & phosphorylate tyrosine on receptor --> SH2 chemical messenger (STAT) binds to tyrosine --> JAKs phosphorylate STATs as well --> STATs dissociate, dimerize --> bind DNA, turn genes on
Describe the TGF-beta receptor kinase signaling pathway.
1) heterodimer receptor (I & II) --> TGF-bta binds to II, serine on type I kinase is phosphorylated --> R-Smad phosphorylated --> Smad activates Co-Smad --> bind DNA, turn on genes
What can mutations in RAS cause?
Describe the tyrosine kinase (EGF) signaling pathway.
GF binds to homodimers, tyrosine kinases dimers autophosphorylate
--> SH2 chemical messenger protein (Grb2) binds
--> SOS protein binds
--> Ras small G-protein binds --> exchanges GDP for GTP to activate its kinase domain
--> binds Raf (MAPKKK) --> MAPKK --> MAPK --> transcription factor
Explain the steps for PI3 pathway in insulin receptors.
Phosphatidylinositol phosphorylated to make PIP2
--> phosphoyrlated by PI3 --> PIP3
--> joins w/ PDK1 --> Akt / activates PKB
Describe the tyrosine kinase (insulin receptor) signaling pathway.
alpha and beta subunits on receptor --> insulin binds
--> kinase domain is autophosphorylated
--> IRSs are phosphorylated
--> SH2-containing proteins can bind to IRS (Grb2 / PLC-gamma/ PI3 kinase)
Describe the kinase receptors signaling pathway. What are the 4 examples?
1) receptor activated --> associated kinase phosphorylates --> signal transducer protein binds to kinase
2) Serine/threonine receptors (TGF-beta); INF or IL/JAK/STAT; Tyrosine receptors (EGF & Insulin)
What's one result of insulin receptor signaling?
increases number of glucose transporters at the plasma membrane
How does the cAMP second messenger pathway work downstream of beta-adrenergic receptor?
norepinephrine binds to receptor
--> --> activated G protein helps adenylyl cyclase catalyzes the conversion of ATP to cAMP
--> binds to regulatory subunit of PKA to activate it
--> glucose production in muscle & liver
Describe the heptahelical (G-protein Coupled) receptor pathway. Examples?
1) 7 alpha helices form barrel in membrane w/ hetero-trimeric G-proteins as associated signal transducers --> GDP exchanged for GTP & activates G-proteins --> cAMP or DAG/IP3 second messenger pathways
2) beta-adrenergic receptors, angiotensin receptors
What are beta-blockers? How do they work?
1) drugs used to treat cardiac arrhythmia
2) bind to beta-androgen receptor (compete against norepinephrine)
How does the cAMP signal get terminated?
cAMP phosphodiesterase reduces cAMP levels by hydrolyzing cAMP to AMP
How does cholera toxin affect the G-protein signaling pathway?
G-alpha-s subunit is covalently modified so that it can't hydrolyze GTP-GDP
--> Adenylyl Cyclase cannot be turned off
--> cAMP is constantly being made
What are the subunit types of G-alpha proteins & what do they do in downstream pathway?
1) s --> stimulates adenylyl cyclase (cAMP)
2) i/o --> inhibits adenylyl cyclase
3) t --> stimulates cGMP phosphodiesterase
4) q/11 --> activates phospholipase C-beta (IP3, DAG)
5) 12/13 --> alters cytoskeletal elements
How does the IP3 / DAG second messenger pathway work downstream of angiotensin receptor?
angiotensin II binds to receptor --> --> activated G protein helps phospholipase C cleave PIP2 into DAG and IP3 --> IP3 opens Ca2+ channel in ER to increase Ca2+--> DAG & Ca2+ activate protein kinase --> other proteins phosphorylated
How does pertussis toxin affect the G-protein signaling pathway?
1) causes G-alpha-i to remain off indefinitely 2) causes covalent modification of G-alpha-i so that it can't bind to GTP --> causes increase in cAMP
How can cell signals be terminated?
1) messengers no longer secreted or degraded 2) receptor desensitized 3) phosphatases 4) GTPases 5) phosphodiesterases