Steroid Hormone Receptors

Question 1

Steroid Hormone Receptors:

‘Superfamily Members’

Answer 1

• Intracellular Receptors
  
  • Androgen Receptor
  • Estrogen Receptor
  • Progesterone Receptor
  • Glucocorticoid Receptor
  • Mineralocorticoid Receptor
  • Vitamin D₃ Receptor
  • Retinoic Acid Receptor
  • Thyroid Hormone Receptor
• Not all mlecules that act at ‘steroid hormone receptors’ are cholesterol derivatives

Question 2

Steroid Hormone Receptor Agonists

Answer 2

• Progesterone
• Testosterone
• Estradiol
• Aldosterone
• Cortisol
• Vitamin D₃
• Retinoic Acid
• Thyroxine

Question 3

Carrier Proteins

Answer 3

• Vitamin D binding protein
• Retinol Binding protein
• Thyroxine binding globulin for thyroid hormones
• sex hormone binding gloculin for steroid androgens and estrogens
• Transcortin for cortisol. Lower affinity for progesterone & aldosterone

Question 4

Receptor Structure

Answer 4

• Steroid hormone receptor superfamily members are structurally similar, all contain:
  
  • Ligand (hormone)-binding domain
  • DNA binding domain
  • Trascription-activting domain

Question 5

Steps in Signaling

Answer 5

1. Ligand is synthesized, secreted, enters circulation and associates with carrier protein
2. Dissociates from carrier to have a concentration of ‘free’ ligand in circulation
3. By diffusion, ligand crosses vasculature cell layers, interstitial fluid and cell membrane to enter the cytosol
4. Receptor binding and release of inhibitory protein
5. Access nucleaus via nuclear pore and dimerize
6. Bind DNA at specific sites
7. Associate with co-factors and initiate transcription
8. RNAs leave nucleus via nuclear pore

Question 6

Common Signaling Mechanism

Answer 6

• Ligands in the blood stream are bound to carrier proteins, which reduce renal excretion
  
  • Ligands remain in vascular circulation for extended periods (hours) until they are excreted (vascular reservoir)
• Ligands are hydrophobic, which necessitates carrier proteins in circulation
• Ligands are lipid soluble and thus can enter cells by diffusion across the lipid membrane.
• Ligands bind to intracellular receptors and activate them
• The activated hormone-receptor complex enters the nucleus, dimerizes (not shown) and minds to a specific sequence on the DNA
• Binding to this specific DNA sequence initiates transcription given that the appropriate set of transcription co-factors are present (2 transcription factors are shown)
• mRNA leaves the nucleaus for translation into protein

Question 7

Receptor Locations

Answer 7

• Intracellular receptors are either located in the cytosol or in the nucleus
  
  • Receptors in the nucleus reside as inactive receptors on the DNA
• In both cases, ligand binding activates the receptor and initiates transcription (the making of mRNA from DNA) given that certain transcription factors are present
  
  • Examples of cytosolic receptors:
    
    • Glucocorticoid receptor (GR)
    • Mineralocorticoid (aldosterone) receptor (MR)
  • Examples of nuclear receptors:
    
    • Thyroid hormone receptor
    • Vitamin D3 receptor
    • Retinoid receptor

Question 8

Specificity of Signaling

Answer 8

• Cell must contain the receptor
• Some ancillary enzymes can be required
  
  • 11B hydroxysteroid dehydrogenase to convert cortisol to cortisone
  • 5a reductase to convert testosterone to dihydrotestosterone
• A specific set of gene regulatory proteins must be present in order to activate transcription. Some of the gene regulatory proteins are cell specific

Question 9

Time course of Signaling

Answer 9

• Signaling via intracellular receptors is slow (minutes to days)
  
  • Long diffusion paths for ligand. Carrier proteins present a reservoir for the ligands (= signaling molecules)
  • Effect requires transcription and translation (and potential subsequent metabolic steps)
  • Termination requires excretion of hormone
    
    • -often as bile after conjugation in the liver

Question 10

Mineralocorticoid Receptor

Answer 10

• Hormone:
  
  • Aldosterone
• Condition:
  
  • Decrease in blood pressure
  • (Renin-Angiotensin-Aldosterone System; RAAS)
• Origin:
  
  • Adrenal cortex
• Carrier protein:
  
  • Albumin
  • Transcortin (less than 25%)
• Receptors:
  
  • Mineralocorticoid receptor
• Effects:
  
  • Na⁺ & H₂O retention / K⁺ excretion
  • Maintenance or increase in blood pressure

Question 11

Aldosterone & Blood Pressure

Answer 11

• Renin is an enzyme, which is released by the kidney (macula densa) into the blood stream in response to a drop in blood pressure
• Renin catalyzes the first of 2 reactions that leads to the production of angiotensin II:
  
  1. Angiotensinogen -> Angiotensin I (renin)
  2. Angiotensin I -> Angiotensin II (angiotensin converting enzyme; ACE)
• Angiotensin II
  
  • Stimulates aldosterone production and release from the adrenal cortex
  • Induces / increases vasoconstriction
  • Enhanves vasopressin secretion
• Aldosterone, along with angiotensin II, stimulates Na⁺ and water retention by the kidney, which conserves blood volume
• Vasoconstriction and the stable/increased blood volume cause an increase in blood pressure
• Aldosterone causes the translation and transcription of genes that code for an apical Na⁺ channel, an apical K⁺ channel and the basolateral Na⁺/K⁺ ATPase
• Increased numbers of these ion transport proteins increases Na⁺ and water retention (and K⁺ excretion)

Question 12

Thyroid Hormone Receptor

Answer 12

• Hormone:
  
  • Thyroxine (T₄)
  • Tri-iodo-thyronine (T₃)
• Condition:
  
  • Cold and/or stress
• Origin:
  
  • Thyroid gland synthesizes and stores the prohormone thyroxine (T₄), from which one iodine is removed to generate the hormone T₃
• Carrier Proteins:
  
  • Thyroxine-binding prealbumin
  • Thyroxine-binding globulin
• Receptor:
  
  • Thyroid hormone receptor
• Effects:
  
  • General increase in metabolism
  • Increased O₂-consumption and ventilation
  • Thermogenesis, mobilization of fat and protein

Question 13

Thyroid Hormone Pathway

Answer 13

• Cold and stress causes the hypothalamus to release TRH (thyrotropin releasing hormone), which reaches the pituitary gland via the blood stream
• TRH causes release of TSH (thyroid stimulating hormone = thyrotropin) from cells in the pituitary
• TSH stimulates the thyroid gland to release thyroid hormone consisting mostly of the prohormone thyroxin (T₄), with some tri-iodo-thyronine (T₃), the biologically active hormone
• T₄ is converted by de-iodinases to T₃, the biologically active form. De-iodinases are located primarily in kidney and liver
• T₃ mediates a general increase in metabolism:
  
  • Increased O₂-consumption and ventilation
  • Thermogenesis, mobilizatino of fat and protein
• T₄ exerts negative feedback by inhibiting TSH release from the piruitary gland

Question 14

Feline Hyperthyroidism

Answer 14

• Presentation:
  
  • Weight loss (despie a good appetite)
  • Rapid heart rate, hyperexcitability
  • Vomiting/Diarrhea
  • Poor hair coat
• Diagnosis:
  
  • Rule out other diseases
  • Determination of plasma levels of T₄
• Prevalence:
  
  • Most common endocrine disorder in older cts
• Suspected causes:
  
  • Cats live longer
  • Exposure to chemicals - polybrominated diphenyl ethers (PBDEs - flame retardants)
• Etiology:
  
  • Feline hyperthyroidism is most often caused by a thyroid adenoma
  • Only 2% of affected cats are diagnosed with thyroi adenocarcnoma
  • One or both lobes of teh thyroid gland may be involved
• Treatment:
  
  1. Methimazole (Tapazol) - inhibits T₃/T₄ production
  2. Surgical removal of the thyroid gland
  3. Radio-iodine treatment with ¹³¹I (¹²⁷I = stable isotope) ¹³¹I emits B-particles that destroy tissue within ~1mm and has a half-life of 8 days

Question 15

Summary

Answer 15

• Steroid Hormone Receptors:
  
  • Most, but not all, ligands are cholesterol derivatives
  • All are intracellular receptors
  • Ligands associate with carrier proteins in circulation
    
    • Accounts for reservoir and for time course of effect
  • Receptors include 3 critical domains
    
    • Hormone binding, DNA binding, Transcription activating
  • Typical interactions with co-activatos or repressors
  • Pathway activity modulated by negative feedback loops