cell phys exam 4 lect 24

Introduction to Receptors and Steroid Hormones

  • Distinct receptors characterized by pharmacology or genetics.
    • Androgen receptor – responds to testosterone and dihydrotestosterone (DHT, a more biologically active form).
    • Cholesterol as a precursor to steroid hormones.
    • Cholesterol (C27 steroid) consists of a tiny polar head group and a larger hydrophobic region embedded in membranes.

Common Steroid Hormone Receptors

  1. Androgen Receptor
    • Ligands: Testosterone, DHT
  2. Estrogen Receptor
    • Ligand: Estradiol
  3. Progesterone Receptor
    • Ligand: Progesterone
  4. Glucocorticoid Receptor
    • Ligand: Cortisol (or corticosterone in rodents/birds)
  5. Mineralocorticoid Receptor
    • Ligand: Aldosterone
  6. Vitamin D Receptor
    • Ligand: Vitamin D

Other Hormonal Receptors Outside the Cholesterol Derivatives

  • Molecules like retinoic acid (Vitamin A) and thyroid hormones have receptors with the same mechanism of action (e.g., they lead to transcription) but are not derivatives of cholesterol.

Drugs Targeting Hormonal Receptors

  • Examples: Flutamide, Clomiphene (Clomid), Tamoxifen, Mifepristone, Dexamethasone, Prednisolone, Spironolactone.
    • Drug selectivity can be a challenge.
    • Ex: Spironolactone can alter water handling or block androgen receptors.
      • Side effects, particularly noticeable in males (e.g., gynecomastia).

Mechanism of Steroid Hormones

  • Primary goal of steroid action: transcription of new proteins.
  • Originates from cholesterol derivatives (C27).
    • Progesterone is early in the synthetic pathway.
    • Pathway leading from cholesterol (C27) through various modifications results in other steroids.

Synthetic Pathway Overview

  1. From C21 Steroids:
    • Corticosterone → Aldosterone (rodents), converted directly to cortisol in other mammals.
    • Difference between cortisol and cortisone is in hydroxylation.
  2. Testosterone Production:
    • Derived through a series of steps and can be modified by 5-alpha reductase into DHT (more biologically active).
    • Finasteride is an inhibitor of 5-alpha reductase, used to treat benign prostatic hyperplasia and male pattern baldness.

Estradiol and Testosterone Interrelation

  • Estradiol is a derivative of testosterone.
  • Importance of testosterone in both males and females for physiological functions.
  • Conversion enzyme: Aromatase, blocked by Letrozole (used in hormone-sensitive breast cancer).

Specific Enzymatic Interactions

  • Cortisol interaction varies between mineralocorticoid and glucocorticoid receptors.
  • 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) converts active cortisol to inactive cortisone in aldosterone-sensitive tissues to prevent disturbance of mineralocorticoid receptor activation.

Lipid Solubility of Hormones

  • Steroid hormones: High lipid solubility (Log P = 3.5 to 4).
  • Cortisol/Aldosterone: Intermediate lipid solubility (Log P = 1 to 2).
  • Cross cell membranes easily due to lipid solubility.

Vitamin D3 and D2 Differences

  • Vitamin D3 (cholecalciferol) is animal-origin; D2 (ergocalciferol) is plant-origin.
  • Biological equivalence debated; supplementation patterns and effects analyzed.
  • Biologically active form: 125-dihydroxycholecalciferol, produced through hydroxylation processes in the liver and kidneys.

Retinoic Acid and Thyroid Hormones

  • Retinoic acid (Vitamin A) receptor can dimerize with various other receptors, influencing transcription factor activity.
  • Thyroid hormones (e.g., T4 and T3) act through similar mechanisms of transcription regulation.

Thyroid Hormone Mechanisms

  • T4 primarily converted to T3 (active form) in liver and kidney.
  • Feedback inhibition from T4/T3 regulates thyroid-stimulating hormone (TSH) secretion from the pituitary.

Hormonal Transport Mechanisms

  • Plasma serves as a carrier for lipid-soluble hormones; various proteins assist in hormone solubility and half-life.
  1. Vitamin D binding protein: Specific for Vitamin D.
  2. Retinol binding protein: For retinol.
  3. Thyroid binding globulin: High affinity, low capacity for thyroid hormones.
  4. Transcortin: For cortisol.
  5. Albumin: Common, low affinity, but high capacity for many steroid hormones in circulation.

Mechanism of Steroid Hormone Action

  • Three major components:
    1. Ligand binding.
    2. DNA binding.
    3. Initiation of transcription.
  • Ligand-receptor binding causes conformational changes, resulting in transcription initiation at targeted DNA sequences.

Process Overview of Hormone Activity

  1. Synthesized and secreted hormone reaches circulation (bound to carrier protein).
  2. Free hormone diffuses into cells and binds to its receptor.
  3. Receptor-ligand complex enters the nucleus and binds to DNA.
  4. Changes transcription rate, leading to protein synthesis.

Summary of Aldosterone Action

  • Aldosterone increases sodium and water retention in the kidneys (through actions in collecting ducts).
  • Mechanism involves rapid SGK protein synthesis and subsequent protein synthesis effects (e.g., ENaC and ROMK).
  • Long-term effects observed in protein expression changes.

Feedback Regulation in the Thyroid Axis

  • T4 feedback to the pituitary reduces TSH secretion, demonstrating the intricate control systems within endocrine axes.