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Cells that express the appropriate receptors bind hormones from the blood. The conformational change in the intracellular part of the receptor triggers signal transduction events including signal amplification and activation of target proteins, which eventually leads to the change in the ____
The complex responses of signal transduction often include the synthesis of a ________, a small molecule that mediates signal transduction inside the cell.
What does the use of second messngers allow?
1) Signal amplification. As many molecules of second messengers can be synthesize in response to a single hormone-receptor complex.
2) Signal transduction to the distant cellular compartments, as second messengers often diffuse relatively freely inside cells
3) Additional mechanisms to control signal intensity by regulating second messenger degradation.
Cyclic GMP (cGMP) and its counterpart cAMP are water soluble second messengers that are deactivated by ______
Hydrolysis of 3' phosphoester bond.
Inositol -1,4,5-triphosphate is a water soluble second messenger. It is degraded by ________
What is DAG?
diacylglycerols. A water insoluble membrane-associated molecule.
What are the three major mechanisms of intracellular signal transductions?
- Receptor tyosine kinase
- cAMP-dependent signaling pathway
- Phosphoinositide pathways
What is the pancreas?
Both an endocrine and exocrine gland, which is located under the stomach. The islet cells produce glucagon, insulin and somatostatin.
What are endocrine glands?
Organs that secrete hormones directly into the blood.
What are exocrine glands?
Organs that secret their products into ducts which lead directly into the external environment.
What does glucagon signal?
It is secreted in response to low glucose concentration in blood. It causes the liver to release glucose through the hydrolysis of glycogen (glycogenolysis) and to synthesize glucose from non-carbohydrate compounds (gluconeogenesis) such as lipids, glycerol, lactate etc.
What is insulin secreted in response to?
It is secreted in response to high glucose concentration and has an effect that is opposite to glucagon's effect. It stimulates liver, muscle, and adipose cells to store glucose in the form of glycogen and fatty acids.
What does somatostatin do?
It inhibits the release of numerous secondary hormones including glucagon, insulin, and growth hormone. It is classified as an inhibitory hormone.
What signaling pathway is typical for activation of cell growth and proliferation by growth factors such as insulin, GH, cytokines and others?
Receptor Tyrosine Kinase (RTK) singaling pathway.
It also has a critical role in the development and progession of many types of cancer.
What are the three major protein components of Receptor tyrosine kinase signaling pathway (RTK)?
Receptor tyrosine kinase (RTK): a transmembrane enzyme that catalyzes phosphorylation of Tyr residues in proteins when activated by binding to a growth factor?
Ras protein: A GTPase which can be indirectly activated by RTK
Cascade of protein kinases: Activated by Ras protein. The cascade multiplies the signal and transfers it to the nucleus.
What occurs in RTK signaling pathway?
The growth factor binds the extracellular portion of RTK and stimulates the intracellular parts of RTK to crossphosphorylate each other.
This activation of RTK causes consequent binding of specific proteins that contain SH2, SH3 and SOS domains to phosphorylated RTK, to each other and GDP-bound Ras protein.
The interaction stimulates replacement of GDP in nucleotide binding pocket of Ras protein with GTP and activates a cascade of protein kinsases (such as Raf, MEK, and/or MAPK protein kineases.
Where does the growth factor bind to Receptor tyrosine kinase?
The N-terminal region is where the growth factor is bound while the C-terminal region contain a catalytically active center which can transfer y phosphate from ATP on a tyrosine residue of a substrate protein.
The conformation change that occurs upon binding reveals the active site and may be accesible to the substrate protein.
What are the four major protein components of cAMP-dependent signaling pathway?
1) G protein-coupled receptors (GPCRs) - Transmembrane proteins that undergo conformational changes in the cytoplasmic portion upon binding a hormone at their extracellular parts
2) Heterotrimeric G protein - Activated by the conformational change in a GPCR
3) Adenylate cyclase - A membrane bound enzyme that synthesizes cAMP from ATP when active.
4) Protein kinase A - Activated by high cytoplasm concentrations of cAMP.
What happens to the heterotrimeric G protein upon the binding of a hormone to a G protein-coupled receptor (GPCR)?
The binding stimulates exchange of GDP into GTP in the Ga subunit of the protein, thus converting Ga into its active form.
Ga dissociates from G-beta-gamma and diffuses along the membrane to adenylate cyclase (AC).
What types of ligands bind to G protein-coupled receptors (GPCRs)?
Odors, pheromones, hormones, and neurotransmitters.
What pathway undergoes receptor densitization?
cAMP dependent signaling.
It reduces their responses when subjected to long-lasting stimulations.
What is the inactive state of heterotrimeric G protein?
- G-alpha has GDP bound to it's current state.
What reaction does Adenylate cyclase (AC) catalyze?
ATP +H2O = cAMP + PPi
What two pathways share both GPCR and heterotrimeric G protein?
- cAMP dependent signaling pathway.
- Phosphoinositide pathway.
What is the difference between cAMP dependent signaling pathway and the Phosphoinositide pathway?
In cAMP dependent signaling, cAMP is the secondary messenger after the G-alpha subunit interacts with Phospholipase C (PLC)
In Phosphoinositide, inositol -1,4,5-triphosphate (IP3) is the secondary messenger after the G-alpha subunit interacts with Adenylate cyclase (AC)
What are the 6 components for Phosphoinositide pathway?
- 1) G protein coupled receptor
- 2) Heterotrimeric G protein
- 3)Phospholipase C (PLC - generates two secondary messengers IP3 and DAG
- 4) Protein Kinase C - stimulated by DAG and activates metabolic enzymes by phosphorylation
- 5) IP3-gated calcium channels - In the sarcoplasmic reticulum, release another second messgener, calcium ion
- 6) Calmodulin (CaM) - Binds Ca2+ and activated CAM-dependent protein kinases.
What is the function of Phospholipase C (PLC)?
Hydrolyzes phosphoester bonds in glycerophospholipids between the oxygen at the third position of glycerol and the phosphate residue.
How is IP3 inactivated?
It can be hydrolysed to IP2 by inositol polyphosphate phosphatase
How is Ca2+ inactivated in RTK signaling?
It may be removed from cytoplasm by Ca2+ ATPase
How might DAG by inactivated in RTK signaling?
DAG and IP3 recombine to form PIP2