Hormone Synthesis and Signaling Pathways Flashcards
What are the classes of hormones?
- Proteins and polypeptides
- Steroids
- Amines
What is the largest class of hormones?
Protein hormones
What differentiates a protein from a peptide?
More than 100 a.a.? Protein
Less than 100 a.a.? Peptide
Describe the secretory pathway for protein hormones
- Nucleus
- RER
- SER
- Golgi
- Exocytosis
What does the constitutive synthesis typically involve (protein hormones)?
Extracellular matrix and plasma membrane components
What is regulated synthesis typically for?
Hormones and enzymes
What are steroid hormones synthesized from?
Cholesterol, specifically from…
- From LDL in blood or de novo from Acetyl-CoA
What is the universal precursor cholesterol is converted to in steroid hormone synthesis?
Pregnenolone
Steroid hormones are lipophilic, what are they regulated by?
Trophic hormones from the pituitary
Characterise the intracellular stores of steriod hormones.
–No intracellular stores of hormone
»Synthesis and secretion closely linked
What are the two tissues associated with steroid hormone synthesis?
Adrenal cortex
Gonads
What hormones are produced in the adrenal cortex?
•Cortisol synthesis
–Glucocorticoid
•Aldosterone
–Mineralocorticoid
•Androgens
What are all amine hormones synthesized from?
Tyrosine
What are the two classes of amine hormones?
Catecholamines and thyroid hormones
What is the order of precursors from tyrosine to epinephrine?
•Tryrosine>DA>NE>Epinephrine
What is dopamine synthesized from? What class of amine hormone is it?
Tyrosine
Catecholamine
Are thyroid hormones lipophilic?
Yes
Where are thyroid hormones synthesized? Stored?
Thyroid gland
Once thyroid hormone is produced and secreted what is it carried by?
Binding protein
T4 has how many iodine residues?
4
What are the adrenal medullary hormones? What are they made from?
epinephrine and norepinephrine - from tyrosine
Adrenal medullary hormones are synthsized and stored in what?
Chromaffin granules, stored on chromogranin
What stimulates the release of adrenal medullary hormones?
Sympathetic innervation
What do circulating hormones exist as?
- Free or unbound
- Associated with binding proteins
What are free/unbound proteins typically? (very generally) Are they water soluble?
Short term or quick acting - peptides and catecholamines
Yes, water soluble
What are hormones typically associated with binding proteins? What are these soluble in?
Long term or slow acting - steroid and thyroid hormones
Fat soluble
Protein hormones activate receptors by binding what cell surface receptors? What are these coupled to?
–GPCR
»Coupled to:
•cAMP
•Phospholipase C
•Phospholipase A2
- Guanylyl cyclase
- RTKs
What does phospholipase C activate?
–Activates G protein which results in activation of phospholipase C (PLC) that cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG).
What does IP3 release? What does this do?
–IP3 releases endoplasmic reticulum Ca2+ stores, thereby activating Ca2+ dependent kinases, including protein kinase C (PKC).
PKC can be activated by?
DAG or IP3
What does phospholipase A2 activate? Resulting in?
–Activates G protein which results in activation of PLA2 which cleaves membrane phospholipids to produces lysophospholipid and arachidonic acid.
What is arachadonic acid converted to?
Eicosanoids
What does receptor tyrosine kinase initiate? What can they phosphorylate?
–Initiate an intracellular cascade of phosphorylation
–Receptors may autophosphorylate themselves
–Receptors may phosphorylate cytoplasmic tyrosine kinases
•Tyrosine-kinase associated receptors
What receptors do steroids hormones bind?
Intracellular, cytosolic or nuclear
What do hormone response elements (HREs) do when activated?
•Once activated, steroid receptors
–dimerize
–bind 5’ DNA sequences (HREs)
–initiate transcription
What do amine hormones bind?
Cell surface receptors
What is the intracellular effect of amine bound receptors due to?
Combination of receptors present
–Adrenoreceptors
–Dopamine Receptors
What do alpha adrenergic receptors interact with?
Norepinephrine
What impact do Alpha 2 adrenergic receptors have on G protein?
Inhibitory
What do alpha 1 adrenergic receptors couple with? What do they do to G protein? What does this lead to?
•Coupled to Phospholipase C
•Activates G protein which results in activation of phospholipase C (PLC) that cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG).
IP3 releases endoplasmic reticulum Ca2+ stores, thereby activating Ca2+ dependent kinases, including protein kinase C (PKC).
What do Beta adrenergic receptors bind? What does this do to G protein?
epinephrine, stimulates G protein
Are dopamine receptors g coupled?
Yes
What are the types of dopamine receptors? Which is G protein stimulatory and which is inhibitory?
DA-1: G protein stimulatory
DA-2: G protein inhibitory
Thyroid hormone is similar to what other hormones?
Steroid hormones
Where is the thyroid hormone receptor located? What does it do upon binding T3?
•Located in nucleus
•Upon binding of T3, dimerizes with Retinoid X Receptor (RXR)
–When T4 enters, deiodinated to T3
•Binds HREs to initiate transcription
Does thyroid hormone elicit nongenomic effects?
Yes
Second messengers are important in what hormone pathways?
Protein and Amine
What doesa protein hormone G-alphaS activate? What is the second messenger?
–Acitvates adenylyl cyclase
–Second messenger is cAMP
What does a protein hormone G-aplhai activate? Second messenger?
–Inhibits adenylyl cyclase
–Reduces cAMP second messenger
What does a protein hormone G-alphaq activate? What is the second messenger?
–Activates phospholipase C
–Second messengers are IP3, DAG, Ca2+
Describe the hormone response time for…
- Ligand-gated ion channels
- G protein coupled receptors
- Kinase-linked receptors
- Nuclear receptors
•Ligand-gated ion channels
–Milliseconds
•G protein coupled receptors
–Seconds
•Kinase-linked receptors
–Seconds, hours or days
•Nuclear receptors
–Hours to days
What are the storage pools for steriod hormones and peptide amine hormones?
Steroid hormones - none
Peptide amine hormones - secretory vesicles
•An 18 y/o female presents to the hospital with nocturia, fatigue, and a 12-lb weight loss over the past four weeks. Her medical history is otherwise unremarkable. Family history is negative for diabetes and she takes no medications. Results from a fasting and a random plasma glucose are 190 mg/dL (normal, 70-100) and 250 mg/dL (normal, 140-200), respectively. Trace amounts of ketones are detected in her urine. The presumptive diagnosis is type 1 diabetes and she begins insulin therapy. After insulin administration, glucose uptake is markedly increased in most of her body’s cells within:
A.Days
B.Hours
C.Minutes
D.Seconds
E.Weeks
D. Seconds
Describe the four steps of activation of insulin receptors.
1.Insulin binds the a subunit of its receptor
2.Autophosphorylation of the b subunit occurs
3.Receptor associated tyrosine kinases are activated
4.Cascade of phosphorylation which increases or decreases the activity of substrates
–Involved in glucose, fat and protein metabolism
What occurs as a result of activation of insulin receptors on the timelines of…
Seconds?
Minutes?
Hours and Days?
•Seconds
–Translocation of multiple intracellular vesicles to cell membranes containing glucose transporters
–Glucose uptake markedly increased and phosphorylated
•Minutes
–Changes in activity levels of intracellular metabolic enzymes due to phosphorylation
•Hours and Days
–Translation and transcription achieving global changes in intracellular metabolic enzymes
What does a mutation in the 5’ UTR do? (3 things)
–Remove inhibitory proteins
–Increase transcription or translation
–Silence or depress expression of the gene
What might we see as a result of a mutation in a hormone gene sequence?
–Could result in
•Incorrect trafficking
•Incorrect folding
–Degradation or inactivation
What can result from mutations in the receptor gene sequence?
–Could result in
•Incorrect trafficking
•Incorrect recycling
•Incorrect DNA interaction
•Constitutive activation or inactivation
What might happen due to mutation in the signaling protein gene sequence?
Same as receptor mutations…
–Could result in
•Incorrect trafficking
•Incorrect recycling
•Incorrect DNA interaction
•Constitutive activation or inactivation
What might a mutation in a hormone response element lead to?
–Could result in
•Activation by the wrong receptor/ transcription factor
•A 16 y/o female is evaluated because of amenorrhea and is found to have a 46, XY karyotype. DNA testing shows a mutation in the testosterone receptor that is characteristic of androgen insensitivity syndrome. Which of the following statements accurately describes sex hormones such as testosterone? They:
A.bind specific membrane receptors.
B.cause release of second messengers from the cell membrane.
C.enhance transcription when bound to receptors.
D.inhibit translation through specific cytoplasmic receptors.
E.interact with DNA directly.
C.enhance transcription when bound to receptors.
Steroid receptors DNA-binding domains are… what relative to one another?
Strikingly similar
If a patient has a substitution of 2 aa in the glucocorticoid receptor results in its binding to the estrogen HRE. What does this mean?
–Glucocorticoids have an estrogen-like effect.
What are the three parts of a steroid hormone receptor?
- Ligand binding domain
- Nuclear localization signal
- DNA binding domain
What does a steroid hormone receptor’s ligand binding domain interact with? Induce?
- Interacts with steroid hormone
- Induces confirmation change
What does a steroid hormone receptor’s nuclear localization signal interact with? Induce?
- Interacts with Nuclear Import Receptors
- Induces translocation into nucleus
What does a steroid hormone receptor’s DNA binding domain nteract with? Induce?
- Interacts with Hormone Response Element (HRE) on DNA
- Induces transcription
What is the typical administration route for proteins?
–Intravenously most common
•Some have been formulated for intranasal, transdermal, pulmonary, buccal, intraocular
What are the routes of administration for steroids?
- Orally
- Transdermally
- IV
- Intramuscularly
How are amines typically administered?
- subcutaneous or intramuscular
- IV
- Orally
•A 35 y/o female notes a lump in her breast and undergoes biopsy that indicates breast cancer. The biopsy tissue is sectioned and shown to react with an antibody to epidermal growth factor receptor-2 (EGFR-2.) Which of the following describes the most likely treatment strategy for this patient?
A.Intravenous infusion of EGF.
B.Intravenous infusion of EGFR-2 antibody.
C.Oral dosing of EGF.
D.Oral dosing of EGF antibody.
E.Oral dosing of EGFR-2 antibody.
B.Intravenous infusion of EGFR-2 antibody.
