M

Chapter 18, lecture 2

Hormone Transport in Blood

  • Two physicochemical categories
    • Water-soluble hormones (peptides, most amines)
    • Hydrophilic → dissolve directly in plasma → circulate freely.
    • Lipid-soluble hormones (steroids, thyroid hormones, nitric-oxide)
    • Hydrophobic → analogous to “oil in water” → require transport (binding) proteins.
  • Functions of transport proteins
    • Render lipid-soluble hormones temporarily water-soluble so they stay in solution.
    • Prevent filtration at the renal glomerulus → slows urinary loss.
    • Provide an intravascular reservoir; hormone can dissociate on demand so the gland need not resynthesise immediately.
    • Extend plasma half-life; some water-soluble hormones also bind carriers to increase longevity.

Free vs. Bound Hormone Fraction

  • After secretion, **≈ 0.1\%–10\% of any lipid-soluble hormone is unbound (“free”).
  • Free fraction is biologically active → diffuses into tissues & binds receptors.
  • Bound fraction is inactive until dissociation.
    • Clinical shorthand: e.g., “free T4” = thyroxine available to enter cells.

Lipid-Soluble Hormone Mechanism of Action (Intracellular Receptors)

  1. Free hormone diffuses across capillary endothelium → interstitial fluid → passes through plasma membrane (lipid-bilayer permeable).
  2. Binds intracellular receptor (cytoplasmic or nuclear).
  3. Hormone-receptor complex undergoes conformational change → migrates to/within nucleus.
  4. Complex binds specific DNA sequences → modifies gene transcription.
  5. Transcription → mRNA → ribosomal translation → new protein synthesis.
  6. Newly synthesised proteins alter cellular activity (e.g., enzymes, structural proteins, transporters).

Water-Soluble Hormone Mechanism of Action (Membrane Receptors & Second Messengers)

  • Cannot cross lipid bilayer; receptor is an integral membrane protein.
  • Binding initiates a signal-transduction cascade (molecular “relay race”).
    1. Hormone = 1st messenger → binds receptor.
    2. Activates trimeric G-protein.
    3. G-protein activates adenylyl cyclase (AC).
    4. AC converts \text{ATP}\;\xrightarrow{AC}\;\text{cAMP} (cyclic AMP) = 2nd messenger.
    5. cAMP activates protein kinase A (PKA) family.
    6. PKA phosphorylates multiple substrate proteins → functional changes (enzyme activity, membrane transport, gene expression, etc.).
  • Typical downstream effects: glycogen synthesis/break-down, lipid catabolism, transcription-factor activation, many others.

Signal Amplification (water-soluble hormones)

  • Unique “multiplier” phenomenon: 1 hormone → ~100 G-proteins → ~10^2 ACs → ~10^3 cAMP molecules → ~10^5 PKAs → ~10^6 phosphorylated proteins.
  • Practical consequence: very low [hormone] elicits large response → explains picomolar endocrine concentrations.

Determinants of Target-Cell Responsiveness

  • [Hormone] in blood: ↑ concentration → ↑ response (within saturation limits).
  • Receptor density on cell surface/intracellularly: up-regulation or down-regulation alters sensitivity.
  • Influence of other hormones simultaneously acting on the same cell (interaction types below).

Types of Hormonal Interactions on a Single Target Cell

  1. Synergistic
    • Hormone-A reinforces hormone-B; combined effect > sum of individual effects.
    • Example: Estrogen + Progesterone during the female reproductive cycle (greater uterine response together).
  2. Permissive
    • Hormone-A requires prior or simultaneous action of hormone-B to exert effect.
    • Example: Oxytocin (milk ejection) requires Prolactin (milk production).
  3. Antagonistic
    • Hormone-A opposes Hormone-B; effects offset each other.
    • Transcript stated: “glucagon decreases and insulin increases glucose” (note: physiologically glucagon raises and insulin lowers blood glucose).

Regulation of Hormone Secretion (Burst-Pattern Release)

  • Endocrine glands release hormones in brief pulses; silence between bursts prevents overstimulation.
  • Three primary stimulus classes:
    1. Hormonal (tropic) stimulation
    • One hormone provokes secretion of another; often forms feedback loops.
    • Example: \text{TSH}{(anterior\;pituitary)} \rightarrow \text{Thyroid gland} \rightarrow \text{T3/T4}; rising T3/T_4 feeds back to inhibit TSH.
    1. Humoral stimulation
    • Plasma levels of ions/nutrients act directly on endocrine cells.
    • Example: Elevated blood glucose → pancreatic β-cells secrete insulin.
    1. Nervous system stimulation
    • Autonomic neurons synapse with endocrine tissue.
    • Example: Sympathetic discharge → adrenal medulla releases epinephrine & norepinephrine (fight-or-flight).

Conceptual & Real-World Connections

  • Pharmacology: Lipid-soluble drugs often given bound to carriers; water-soluble drugs may exploit second-messenger systems for rapid onset.
  • Renal physiology: Binding proteins reduce glomerular filtration → relevant in proteinuria states.
  • Clinical labs: "Free" vs "Total" hormone assays guide diagnosis (e.g., free-T4 in thyroid disease).
  • Pathology: Mutations in G-proteins, AC, or kinases can mimic endocrine excess (e.g., McCune–Albright syndrome).