Hormone Synthesis and Signaling

Question 1

Classes of Hormones

Answer 1

Proteins and polypeptides
Steroids
Amines

Question 2

Protein Hormones- sizes

Answer 2

> 100 aa referred to as proteins

Question 3

Protein Hormones- secretory pathway

Answer 3

Secretory Pathway
•	Nucleus
o	mRNA synthesized and released through gated transport
•	RER
o	Synthesized from mRNA
o	Preprohormones
•	SER
o	Post-translational modifications
o	Cleaved to prohormones
•	Golgi Apparatus
o	Packaged into secretory vesicles
o	Cleaved within vesicles to hormones
•	Exocytosis

Question 4

Constitutive vs. Regulated (protein hormones)

Answer 4

• Constitutive synthesis generally involves extracellular matrix and plasma membrane components
• Regulated synthesis generally for hormones and enzymes (Regulated most often at the level of transcription or exocytosis)

Question 5

Steroid Hormones

Answer 5

 Synthesized from cholesterol (From LDL in blood or de novo from Acetyl-CoA. Cholesterol is converted to the universal precursor Pregnenolone)
 Lipophilic
• Regulated by trophic hormones from the pituitary (No intracellular stores of hormone, Synthesis and secretion closely linked)

Question 6

Two tissues of Steroid hormones

Answer 6

o Adrenal Cortex (Cortisol synthesis: Glucocorticoid, Aldosterone: Mineralocorticoid, Androgens)
o Gonads: Ovary (Estrogen or progesterone), Testes

Question 7

What are amine hormones synthesized from?

Answer 7

tyrosine

Question 8

Dopamine

Answer 8

• an amine hormone synthesized from tyrosine.

Tryrosine>DA>NE>Epinephrine
• Acts as a neurotransmitter
• Endocrine role not well defined
o Catecholamine

Question 9

Thyroid Hormones: classification and 8 steps of synthesis

Answer 9

• Amine. Also classified as lipophilic
• Synthesized and stored in thyroid gland
o Mostly within the follicular lumen and under the control of follicular cells
1. Follicular cell secretes Iodine and thyroglobulin into the lumen
2. Iodination of tyrosine residues on thyroglobulin
3. Conjugation of iodinated tyrosine residues to the iodinated tyrosine residues on thyroglobulin creates T3 and T4 linked to thyroglobulin
4. Endocytosis into follicular cells
5. Proteolysis of T3 and T4 from thyroglobulin in endolysosome
6. Secretion of T3 and T4 into circulation
7. Carried by binding protein
8. Liver and other target tissues deionate T4 to T3 (lower in conc. but main effector as it has more affinity for receptor)

Question 10

Adrenal Medullary Hormones

Answer 10

• Epinephrine and Norepinephrine (Catecholamines) (Tryrosine>DA>NE>Epinephrine)

• Synthesized and stored in chromaffin granules
• Stimulated release by sympathetic innervation (Circulating hormone cannot exert negative feedback, Control centers only detect end physiologic effect– Ex. Blood pressure via stretch receptor)

Question 11

Two ways Circulating Hormones can exist

Answer 11

• Free or Unbound (Short term or quick acting, Water soluble–Peptides and catecholamines)
• Associated with Binding Proteins (Long term or slow acting, Fat soluble– Steroid and thyroid hormones. Ex. Thyroid Hormones: Extends half-life and creates a reservoir within blood)

Question 12

Receptor activation by protein hormones

Answer 12

bind cell surface receptors: GPCR, Guanylyl cyclase, receptor tyrosine kinase

Question 13

GPCR

Answer 13

 Coupled to cAMP
• Activates G protein which results in activation (s) or inhibition (alphas) of adenylyl cyclase, thereby affecting intracellular [cAMP] which activates protein kinase A (PKA) to phosphorylate substrates
 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).
• DAG also activates PKC
 Coupled to Phospholipase A2
• Activates G protein which results in activation of PKA2 which cleaves membrane phospholipids to produces lysophospholipid and arachidonic acid.
• Arachadonic acid is converted into eicosanoids

Question 14

Guanylyl cyclase

Answer 14

 Receptor itself is a guanylyl cyclase increasing intracellular [cGMP]

Question 15

Receptor Tyrosine Kinase

Answer 15

 Initiate an intracellular cascade of phosphorylation
 Receptors may autophosphorylate themselves
 Receptors may phosphorylate cytoplasmic tyrosine kinases (Tyrosine-kinase associated receptors)

Question 16

Steroid hormones (signaling)

Answer 16

• Bind intracellular receptors (mostly)
o Cytosolic
o Nuclear
• Hormone Response Elements (HREs)
o Once activated, steroid receptors
 dimerize
 bind 5’ DNA sequences (HREs)
 initiate transcription
• Specificity depends on presence of receptor
o HREs very similar
• Dissociation of the receptor may occur due to chemical modifications which change its confirmation
• After dissociation, a receptor may return to the nucleus or be degraded
• Receptor expression is not induced by the steroid hormone itself
• Nongenomic signaling can occur

Question 17

Amine Hormones signaling

Answer 17

• Bind cell surface receptors
o Intracellular effect of receptor activation due to combination of receptors present
(adrenoreceptors, dopamine receptors)

Question 18

Adrenoreceptors (for amine hormones)

Answer 18

• GPCRs
• alpha-adrenergic (Norepinephrine, alpha 2: G protein inhibitory (Galphai), alpha 1: 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).
• Beta-adrenergic (Epinephrine, G protein stimulatory (G alpha s)

Question 19

Thyroid Hormone signaling

Answer 19

is similar to steroid hormones
o Thyroid Hormone Receptor: Located in nucleus. Upon binding of T3, dimerizes with Retinoid X Receptor (RXR). When T4 enters, deiodinated to T3
 Binds HREs to initiate transcription
o Elicits nongenomic effects too

Question 20

What is a hormone response element?

Answer 20

a sequence of DNA.

When you see “element,” think DNA.

Question 21

What does G stimulatory mean?

Answer 21

they increase the concentration of cAMP

Question 22

Hormone response time

Answer 22

Ligand-gated ion channels- Milliseconds
G protein coupled receptors- Seconds
Kinase-linked receptors- Hours to days
Nuclear receptors- Hours to days

Question 23

Mutations in Hormone receptors

Answer 23

In hormone gene sequence
- Could result in, Incorrect trafficking, Incorrect folding (Degradation or inactivation)

In receptor gene sequence
-Could result in Incorrect trafficking, Incorrect recycling, Incorrect DNA interaction, Constitutive activation or inactivation

In signaling protein gene sequence
- Results same as receptor

In hormone response element
- Could result in Activation by the wrong receptor/ transcription factor

Question 24

Mutations in Steroid Receptors

Answer 24

Steroid receptors DNA-binding domains are strikingly similar to one another.
Mutations in this region can greatly alter hormone function
Example:
Substitution of 2 aa in the glucocorticoid receptor results in its binding to the estrogen HRE.
Result: Glucocorticoids have an estrogen-like effect.

Question 25

Administration Routes for Protein hormones

Answer 25

Intravenously most common

Some have been formulated for intranasal, transdermal, pulmonary, buccal, intraocular

Question 26

Administration routes for steroid hormones

Answer 26

Orally
Synthetic cortisol
Synthetic progesterone and estradiol

Transdermally
Testosterone
Cortisol
Estradiol/ progesterone

Intravenously 
Testosterone
Estradiol
In emergency situations
(Addison’s disease)
During surgery
(Anti-inflammatory)
Intramuscular
Progesterone

Question 27

Administration routes for amine hormones

Answer 27

Subcutaneous or IM: Epinephrine
Intravenous: Norepinephrine, Dopamine
Orally: Thyroid Hormones