mol endocrinol_51

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’



Where do the hormones come from?



Target cells await for the arrival of the hormoneshttp://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookEND



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.



Hormone Receptors:I. Cell surface receptors

II. Intracellular receptors

http://personal.tmlp.com/Jimr57/textbook/chapter3/cmf3.ht

Cytoplasmic/nuclear receptors



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



How do hormones change their target cells ?

• Activation of enzymes and other dynamic

molecules

(Amino acid-based hormones)

• Modulation of gene expression

(Steroid hormones)



http://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookEN



Amino acid based hormones: cell surface receptors



fluid & electrolyte balance

glucose production & proteinmetabolism

sexual development & control inpregnancy

Steroid hormones:

I. Mineralocorticoids:

II. Glucocorticoids:

III. Sex steroids:



Steroid synthesis



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



Mechanism of steroid hormone action

I.



II.



http://www.people.virginia.edu/~rjh9u/gif/gnrganim.gif



Structure of steroid hormone receptors



Estrogen receptorBound estrogen(blue)

Progesterone receptorBound progesterone(red



Steroid hormone-receptor complex bound to DNA sequence

called ‘hormone response element’



2. Amino acid-based (peptide) hormones

- adrenal cortex, ovaries, testes

- enter the cell freely (lipid)

How does one steroid affect so many genes??



Steroid hormones are typically eliminated byinactivating metabolic transformations and excretion

in urine or bile.

Steroid catabolism

“Conjugation”



Conjugated products

Excreted in urine

Steroid glucuronide Steroid sulphate



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



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



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



• 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



• 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



NUCLEAR RECEPTOR SIGNALLING MECHANISMS



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.



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”



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



Mechanism of action of p160 nuclear receptor coactivators.



Tissue-selective ligands

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