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8/14/2019 Mol endocrinol_51
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Chemical regulator of cellular function
Synthesized in specific cells in endocrine glands
Released into the circulation
Acts on specific target tissues
Effects are of physiologic importance to the organism
‘Hormone’
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Where do the hormones come from?
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Target cells await for the arrival of the hormoneshttp://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookEND
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Endometrial cells from the uterus of a guinea pig; 15 minutes after an
injection of radioactive progesterone. http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/S/SteroidREs.
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Hormone Receptors:I. Cell surface receptors
II. Intracellular receptors
http://personal.tmlp.com/Jimr57/textbook/chapter3/cmf3.ht
Cytoplasmic/nuclear receptors
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Classification of Hormones Based on their Structure
Derived from cholesterol
Steroid hormones: cortisol, aldosterone,testosterone, estrogens, progesterone
Vitamin D derivatives: active metabolites
synthesized from dietary vitamin D
Derived from amino acids Single amino acids: thyroxine(tyrosine), epinephrine (phenylalanine)
Peptides: ACTH, growth hormone,
insulin, parathyroid hormone, etc Glycoproteins: LH, FSH, TSH, etc
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How do hormones change their target cells ?
• Activation of enzymes and other dynamic
molecules
(Amino acid-based hormones)
• Modulation of gene expression
(Steroid hormones)
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http://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookEN
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Amino acid based hormones: cell surface receptors
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fluid & electrolyte balance
glucose production & proteinmetabolism
sexual development & control inpregnancy
Steroid hormones:
I. Mineralocorticoids:
II. Glucocorticoids:
III. Sex steroids:
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Steroid synthesis
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Transport of Steroid hormones
Protein Steroid specificity
Albumin
Cortisol-binding globulin
(CBG)
Sex hormone-binding globulin
(SHBG)
Nonspecific, carries many steroids
Cortisol,progesterone
Testosterone, estradiol
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Mechanism of steroid hormone action
I.
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http://www.people.virginia.edu/~rjh9u/gif/gnrganim.gif
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Structure of steroid hormone receptors
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Estrogen receptorBound estrogen(blue)
Progesterone receptorBound progesterone(red
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Steroid hormone-receptor complex bound to DNA sequence
called ‘hormone response element’
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2. Amino acid-based (peptide) hormones
- adrenal cortex, ovaries, testes
- enter the cell freely (lipid)
How does one steroid affect so many genes??
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Steroid hormones are typically eliminated byinactivating metabolic transformations and excretion
in urine or bile.
Steroid catabolism
“Conjugation”
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Conjugated products
Excreted in urine
Steroid glucuronide Steroid sulphate
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Physical Characteristics of Hormones
Characteristic
Hormones from
Amino Acids
Hormones from
Cholesterol*
Solubility Hydrophilic Lipophilic
Circulation in plasma Free-ionized Bound to proteins
Half life in plasma Short (minutes) Long (hours-days)
Concentration inplasma
Very low (nM or pM) Low (μM)
*includes thyroid hormones
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Biosynthesis of Hormones
Characteristic
Hormones from AminoAcids
Hormones fromCholesterol*
Method of synthesis As polypeptide frommRNA
Multi-enzyme pathway
Storage after synthesis
Secretory granules ingland of origin
Released oncompletion of
synthesis
*includes thyroid hormones
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Mechanism of Action of Hormones
Characteristic Hormones from AminoAcids
Hormones fromCholesterol
Receptor site on target
tissue
External cell
membrane
Cell cytoplasm or
nucleus
Action site Cell membrane Cell nucleus
Mechanism of action Changes the cellmembrane, usuallywith formation of anintracellular messenger
Changes geneexpression, affectsmRNA and proteinsynthesis
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• Multiple receptors for the same hormone can also derive from a
single gene either by alternative promoter usage or alternative splicin
g (e.g.,TR β 1 and β 2).
• some receptors can mediate the signal of multiple hormones.
- mineralocorticoid (aldosterone) receptor (MR) has equal affinity for cortisol
and probably functions as a glucocorticoid receptor in some tissues, such as the brain
- The androgen receptor (AR) binds and responds to both testosterone and
dihydrotestosterone (DHT)
Subclasses of Nuclear Receptor Ligands
Classical Hormones
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• hypothyroidism due to iodine deficiency• pituitary gland fail to synthesize hormone• deficiency or pharmacological inhibition of enzyme
(testosterone to DHT, T4 to T3,testosterone to estradiol)
• reduction of enzyme activity for hormone inactivation
11- -hydroxysteroid dehydrogenase (11 -OHSD): inactivate cortisol
Regulation of ligand level
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NUCLEAR RECEPTOR SIGNALLING MECHANISMS
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Fig. 3. Conserved structure of the ligand binding domain of nuclear receptors. The crystal structure of the progesteronereceptor (PR) LBD bound to progesterone (ball and stickstructure). Helices H1, H3, H9, H10, H11, and H12 are labeled.Helix 12 shown with darker shading contains the core AF-2 and
folds over the ligand-binding pocket.
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Target gene recognition by nuclear receptors
• Hormone response elements (HREs): c-terminal of NR• 66-68 aa, 2 zinc fingers (4 cys-Zn2+ )
• specificity: P-box, half- site ( next slide)
• receptor dimerization: TR, VDR, RAR, LXR, PPAR---- “RXR”
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Ligand activated gene transcription
• coativators: DNA unwinding (HAT)
-best known coactivators: p160 (see fig)
- interact with histone, recruit GTFs
Repression of gene transcription by unliganded receptors
• Corepressors (~270 kda)
-Nuclear receptor corepressor (N-CoR)
-Silencing mediator for retinoid and thyroid receptors (SMRT)
• does not possess but recruit HDACs• inhibit GTFs directly
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Mechanism of action of p160 nuclear receptor coactivators.
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Tissue-selective ligands