What are some minor factors that control release of aldosterone? (2)
Postural changes (renin increases in upright position)
Natriuretic peptides (ANP, BNP) released by myocardial cells to inhibit renin and aldosterone
What is the primary regulator of adrenal androgens? (1)
What other factors may affect adrenal androgens? (4)
Other: -Newborn -Pre-puberty -Age (gradual fall after 30) -Illness (decrease)
In several illness, what happens to cortisol and DHEA?
Can DHEA replacement be useful?
Some evidence shows that women with adrenal insufficiency will benefit:
Which 4 factors determine the physiological effects of a hormone?
Tissue-specific expression of receptor
Number of receptors expressed per cell
Mutational changes in receptor structure
Where might an endocrine receptor be located (2)?
Which types of hormones typically bind these receptor types?
Tyrosine kinase receptor
G-protein coupled receptor
Nuclear receptor: Steroid
Tyrosine kinase receptor: Peptide
G-protein coupled receptor: Peptide
Regarding ligands for nuclear receptors, provide some of their properties.
Non-protein molecules (not encoded in genome), but rather from dietary, environmental or metabolic precursors
Cross plasma membrane passively or via transport proteins
Why are nuclear receptors highly conserved?
What part of nuclear receptors is highly conserved? **
Because structure dictates function
** DNA binding domain is highly conserved**
Give 5 requirements of nuclear receptor structure.
Nuclear localization signal
DNA binding domain
What is the name of the sequence in the promoter of the target gene that is bound by a nuclear receptor dimer?
How is its specificitydetermined? (3)
Hormone response element
Nuclear specificity: -Sequence of hexameric half sites -# of bases separating the half sites -Adjacent DNA sequences
What are the structural components of nuclear receptors? (3)
DNA binding domain
Ligand binding domain
What motif binds to the hormone response elements in the DNA binding domain of nuclear receptors?
Zinc finger motif
Nuclear receptors play a major role in physiology. Despite binding chemically unrelated ligands, how are the receptorsrelated?
Nuclear receptors are structurally related
Fill in the blank:
Nuclear receptors are essentially lignan-regulated __________ factors.
Nuclear receptors are essentially ligand-regulated transcription factors
Biological effects are occur through transcriptional regulation (gene regulation)
What are the 3 classes of nuclear receptors?
Class 1: Steroid receptor family
Class 2: Thyroid/Retinoid receptor family
Class 3: Orphan nuclear receptors
Name 5 classic steroid receptors (Class I)
Describe the steps of steroids binding steroid receptors (About 6 steps)
Unbound steroid receptors are in cytoplasm, complexed with heat shock proteins (HSPs)
Ligand binding results in dissociation of the HSPs, exposing the nuclear dimerization domain
Dimerization of 2 steroid receptors occurs
The dimer then translocates to the nucleus and associates with the hormone response element
Receptor dimer associates with coactivator or corepressor molecules
Gene transcription is altered
For the Thyroid/Retinoid (Class II) receptors, describe the 2 states that dictate the mechanism of action.
The thyroid/retinoid receptor is within the nucleus
In the unliganded state, the unbound receptor is associated with a repressor complex that represses gene transcription: -gene transcription is repressed by histone deacetylation
In the liganded state, the bound receptor is associated with a coactivator complex, that promotes gene transcription: -gene transcription is activated by histone acetylation
Name 4 of the metabolite activated receptors (Thyroid/retinoid receptor family)
Thyroid hormone receptor
Retinoic acid receptor
Vitamin D receptor
Describe receptors in the thyroid receptor family relative to the steroid receptors
About the thyroid receptors:
Unlike steroid receptors, they do not associate with HSPs in the cytoplasm
They form heterodimers (in the absence of a ligand)
Unliganded receptors bind to HRE and act as repressor
Liganded receptorsupregulate gene expression
What are Orphan nuclear receptors (Class III)?
Ligand is undefined or may not be required for activation
How do nuclear receptors relate to human disease? (give 4 examples related to the receptor classes discussed)
Glucocorticoid receptor: Mutations in GR receptor lead to reduced sensitivity of receptor for cortisol -hypertension, hypokalemia, virilization, sexual precocity
Thyroid receptor: Mutations in TRβ gene lead to reduced binding of T3 to TRβ -symptoms of both hypothyroidism and hyperthyroidism
PPARγ receptor:Mutation in the LBD of PPARγ (heterozygous) -lipodystrophy, severe insulin resistance, hypertension, hepatic steatosis, early atherosclerosis, diabetes -PPARγ agonists used as oral antidiabetic agents that promote lipid storage and improve insulin resistance
Orphan receptor HNF4α: Leads to mature onset diabetes of the young (MODY) -Rare monogenic form of diabetes, onset age less than 25, non-obese, abnormal insulin secretion or β-cell mass
For each receptor/drug, list conditions that are targeted with therapies:
Thyroid hormone (TR)
Vitamin D (VDR)
Retinoic Acid (RAR)
Glucocorticoid (GR): anti-inflammation
Estrogens (ER): hormone therapy in menopause
Thyroid hormone (TR): hypothyroidism
Fibrates (PPARα): dyslipidemia
Thiazolidinediones (PPARγ): type 2 diabetes
Vitamin D (VDR): preventative for rickets, diabetes, cancer