BCM - Hormone Signaling Pathways Flashcards
What is endocrine signaling?
When a signaling molecule is released by a cell distant from its target and is transported via the blood stream to the target cell
Ex: epinephrine
What is paracrine signaling?
When a signaling molecule released by one cell diffuses to a neighboring target cell
Ex: Testosterone
What is autocrine signaling?
When a signaling molecule acts on the same cell that it is secreted from.
Ex: Interleukin-1
What is juxtacrine signaling?
When a signaling molecule stays attached to the secreting cell and binds to a receptor on an adjacent target cell
Ex: Heparin-binding epidermal growth factor
How do hydrophilic and hydrophobic hormones compare in terms of half life?
Hydrophilic hormones have very short half lives, seconds to minutes
Hydrophobic hormones have longer half lives, hours to days
Where does the G protiein get its name from?
G protein receptors have intrinsic GTPase activity, which allows it to deactivate itself by hydrolyzing the GTP to GDP and Pi
What specific enzymes/proteins activate and deactivate G Proteins?
Guanine Exchange Factor (GEF) - Causes activation by hydrolyzing Exchanging a Phosphate group from one GTP molecule to the GDP moelcule bound the Alpha Subunit, forming GTP-bound activated Alpha Subunit
GTPase Activating Protein (GAP) - Causes deactivation by hydrolyzing the GTP bound to the Alpha subunit into GDP
Describe the secondary messenger cascade of Gs GPCRs
Ligand binds to GPCR, GDP on alpha subunit is converted to GTP, activating the subunit
Activated alpha subunit then activates membrane-bound Adenylyl cyclase
Adenylyl cyclase converts ATP to cAMP
cAMP activates PKA
PKA phosphorylates target proteins
Describe the secondary messenger cascade of Gi GPCRs
Ligand binds to GPCR, GDP on alpha subunit is converted to GTP, activating the subunit
Activated alpha subunit then inactivates the membrane-bound Adenylyl Cyclase
This inhibits cAMP from being produced and thus also prevents activation of PKA
Describe the secondary messenger cascade of Gq GPCRs
Ligand binds to GPCR, GDP on alpha subunit is converted to GTP, activating the subunit
Activated alpha subunit then activates Phospholipase C (PLC)
PLC then activates PIP2, causing it to split into IP3 and DAG
IP3 causes an increase in intracellular Ca2+
Intracellular Ca2+ and DAG both activate PKC, which phosphorylates target proteins
Describe the secondary messenger cascade of Gt GPCRs
Light activates the GPCR, causing the GDP on the alpha subunit to be converted to GTP, activating the subunit
Activates alpha subunit then activates cGMP PDE (phosphodiesterase) which converts cGMP to 5’-GMP
What are some structural features of insulin?
Insulin is made up of two polypeptide chains (an A chain and a B chain)
There are two disulfide bonds connecting the two chains
There is a third disulfide bond found within the A chainf
A chain is shorter than B chain
Describe the process of insulin synthesis and secretion
Preproinsulin mRNA is translated into preproinsulin protein
Preproinsulin is transported to the ER lumen
Protease cleaves preproinsulin, forming proinsulin
Proinsulin is folded and transported to the Golgi
While in the Golgi, the proinsulin is packaged into granules
Within the granules, proteases cleave the proinsulin, forming a collection of insulin and C peptides
While stored in the granules, insulin forms into hexameric crystals (3 dimers bound together)
When Beta cell is signaled to do so, insulin and C peptide are secreted together into the blood.
What are the two phases of insulin secretion?
Readily Releasable Pool (RRP) - first release (less than 5% of stored insulin) is rapidly secreted upon stimulation by glucose
Reserve Pool - second release (95% of stored insulin) granules must be mobilized before they canbe secreted
How does insulin get secreted?
Glucose causes ATP to increase
Increased ATP inhibits ATP sensitive K-ATP channels
Inhibition of K-ATP channels causes membrane depolarization, activating Ca2+ channels
Ca2+ enters the cell causing insulin granules to be secreted
How does insulin signaling cause Glucose uptake in cells through the RAS independent pathway?
Insulin binds to Receptro Tyorsine Kinase, causing dimerization of the receptor and phosphorylation fo tyrosine kinase domains.
Active tyrosine kinase domains phosphorylate, thus activating, IRS-1
Activated IRS-1 recruits PI 3-kinase
PI 3-kinase activates PKB
PKB phosphorylates target proteins which promotes GLUT4 movement to plasma membrane (in muscle and adipose cells) and promotes glycogen synthesis
What is the RAS-dependent pathway of insulin signaling?
Insulin binds to Receptor Tyrosine Kinase, causing dimerization and autophosphorylation of intrinsic tyrosine kinase domains
Activated tyrosine kinase domains phosphorylate IRS-1
Activated IRS-1 recruits GRB-2
GRB-2 activates RAS and MAP kinase pathway
Results in activation of Glucokinase enzyme, thus promoting glycolysis and glycogen synthesis
How is insulin signal terminated?
Receptor is internalized in target cells by endocytosis
Is either destroyed or recycled back to the plasma membrane
What is insulin resistance?
Failure of normal amounts of insulin to elicit the uptake of an adequate amount of glucose
Can be caused by downregulation of insulin receptors or defects in insulin signaling (inability to move GLUT4 transporters to plasma membrane in target tissue)
What are orphan receptors?
Nuclear receptors found by DNA sequencing, whose ligands have yet to be discovered
When a ligand to an orphan receptor is discovered, it becomes an “adopted” orphan receptor
What are the domains that make up nuclear receptors?
Ligand Binding Domain (LBD)
Activation Function 1 Domain (AF1)
DNA Binding Domain (DBD)
Distinguish the Estrogen Receptors
ER-alpha (first to be discovered) is expressed most abundantly in the female reproductive tract (especially the uterus, vagina, and ovaries)
- Also expressed in mammary glands, hypothalamus, endothelial cells, and vascular smooth muscle
ER-beta is expressed most abundantly in the ovaries and prostate
- Also expressed in lung, brain, bone, and vasculature
Many cells express both receptors
How estrogen signaling work?
Estrogen binds to nuclear receptor, causing dimerization.
Dimerization promotes HAT (Histone Acetyl Transferase) activity - promotes gene expression
HAT activity activates transcription
What is Tamoxifen and how does it work?
Is an estrogen antagonist, used to treat breast cancer
Tamoxifen is metabolized by liver Cyt P450 to 4-hydroxy-tamoxifen, which binds to ER and promotes HDAC (Histone Deacetylase) activity
HDAC activity inhibits transcription
