Hormone Synthesis and Signaling Flashcards
Classes of Hormones
Proteins and polypeptides
Steroids
Amines
Protein Hormones- sizes
> 100 aa referred to as proteins
Protein Hormones- secretory pathway
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
Constitutive vs. Regulated (protein hormones)
- 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)
Steroid Hormones
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)
Two tissues of Steroid hormones
o Adrenal Cortex (Cortisol synthesis: Glucocorticoid, Aldosterone: Mineralocorticoid, Androgens)
o Gonads: Ovary (Estrogen or progesterone), Testes
What are amine hormones synthesized from?
tyrosine
Dopamine
- an amine hormone synthesized from tyrosine.
Tryrosine>DA>NE>Epinephrine
• Acts as a neurotransmitter
• Endocrine role not well defined
o Catecholamine
Thyroid Hormones: classification and 8 steps of synthesis
• 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)
Adrenal Medullary Hormones
• 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)
Two ways Circulating Hormones can exist
- 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)
Receptor activation by protein hormones
bind cell surface receptors: GPCR, Guanylyl cyclase, receptor tyrosine kinase
GPCR
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
Guanylyl cyclase
Receptor itself is a guanylyl cyclase increasing intracellular [cGMP]
Receptor Tyrosine Kinase
Initiate an intracellular cascade of phosphorylation
Receptors may autophosphorylate themselves
Receptors may phosphorylate cytoplasmic tyrosine kinases (Tyrosine-kinase associated receptors)
Steroid hormones (signaling)
• 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
Amine Hormones signaling
• Bind cell surface receptors
o Intracellular effect of receptor activation due to combination of receptors present
(adrenoreceptors, dopamine receptors)
Adrenoreceptors (for amine hormones)
• 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)
Thyroid Hormone signaling
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
What is a hormone response element?
a sequence of DNA.
When you see “element,” think DNA.
What does G stimulatory mean?
they increase the concentration of cAMP
Hormone response time
Ligand-gated ion channels- Milliseconds
G protein coupled receptors- Seconds
Kinase-linked receptors- Hours to days
Nuclear receptors- Hours to days
Mutations in Hormone receptors
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
Mutations in Steroid Receptors
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.
Administration Routes for Protein hormones
Intravenously most common
Some have been formulated for intranasal, transdermal, pulmonary, buccal, intraocular
Administration routes for steroid hormones
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
Administration routes for amine hormones
Subcutaneous or IM: Epinephrine
Intravenous: Norepinephrine, Dopamine
Orally: Thyroid Hormones
