Bio lecture 3

• Hormones


  Natural organic substances that regulate growth, metabolism and other functions of an organism
• Hormones

  • They are secreted in small amounts by one type of tissue (called endocrine glands) and carried directly by the blood to act in another tissue (called target tissue) elsewhere in the body
  • They can also act on adjacent cells (paracrine action) and on the cells in which they were synthesized (autocrine action) without entering the systemic circulation
• Target cell


  Any cell in which the hormone (ligand) binds to its receptor, whether or not a biochemical or physiologic response has yet been determined

  
• Characteristics of hormones

  • They are present at very low concentrations in the blood in the range of 10-15 to 10-9 mol /L
  • They initiate their biologic effects by binding to specific receptors on or in target cells
  • Hormone-induced actions terminate when the effector dissociates from the receptor
  • They have short half-lifetime in blood due to their rapid inactivation
• Hormone action


  They can alter plasma membrane permeability, stimulate protein synthesis, activate or deactivate enzyme systems, induce secretory activity, or stimulate mitosis
• Ways to classify hormones


  • Chemical composition
  • Solubility properties
  • Location of receptors
  • The nature of the signal used to mediate hormonal action within the cell

  
• Chemical composition of hormones

  • Derived from cholesterol (glucocorticoids, mineralocorticoids, androgens, estrogens, progestins, 1,25(OH)2-D3)
  • Amino acid derived (catecholamines, thyroid hormones)
  • Polypeptides (TRH, ACTH, PTH, GH, insulin)
  • Glycoproteins (FSH, LH, TSH, CG)

  
• Group I hormones


  Interact with an intracellular receptor
• Group II hormones


  Interact with receptor recognition sites located on the extracellular surface of the plasma membrane of target cells

  
• Mechanism of action of group I hormones

  1. Lipophilic hormone traverses the plasma membrane and binds to cytoplasmic or nuclear receptor

  2. The hormone-receptor complex binds to specific region of DNA called hormone-receptor element (HRE) and activates or inactivates specific genes, resulting in changes in the amounts of specific proteins, which influence the metabolic processes

  
• Types of membrane receptors for group II hormones

  • Ion channel-linked receptor
  • G-protein coupled receptor
  • Enzyme-linked receptor

  
• Mechanism of action of G-protein coupled receptors


  1. In the absence of hormone, the heterotrimeric G-protein complex (α,β,γ) is in an inactive GDP-bound form

  2. On binding of hormone to the receptor, there are conformational changes within the receptor, resulting in exchange of GDP with GTP on the α subunit, after which α and βγ dissociate

  3. The α subunit binds to and activates the effector (E), which can be adenylyl cyclase, Ca2+, phospholipase Cβ, or cGMP phosphodiesterase

  
• Mechanism of action using cAMP as second messenger

  1. Hormone (first messenger) binds to its receptor (GPCR), which then binds to a G protein

  2. The G protein is activated as it binds GTP, displacing GDP

  3. Activated G protein activates the effector enzyme adenylate cyclase

  4. Adenylate cyclase generates cAMP (second messenger) from ATP

  5. cAMP activates protein kinase A (PKA), which then cause cellular effects by phosphorylation of several proteins and enzymes

  
• Mechanism of action using calcium and phosphoinositides as second messengers


  1. Binding of hormone to GPCR activates Phospholipase C enzyme which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol trisphosphate (IP3) and 1,2-diacylglycerol (DAG)

  2. IP3 increases release of Ca2+ from intracellular storage sites in the endoplasmic reticulum

  3. The resulting elevations of cytosolic Ca2+ activate Ca2+-calmodulin–dependent kinases and many other Ca2+-calmodulin–dependent enzymes
• Mechanism of action using cGMP as second messenger


  1. Cyclic GMP is formed from GTP by the action of the enzyme guanylate cyclase

  2. Membrane bound guanylate cyclase is activated by atrial natriuretic factor (ANF), leading to effects like natriuresis, diuresis, inhibition of aldosterone secretion, and vasodilatation

  3. Soluble guanylate cyclase is activated by compounds like nitroprusside, nitroglycerin, nitric oxide and sodium nitrate, leading to smooth muscle relaxation and vasodilation

  4. cGMP activates cGMP-dependent protein kinase (PKG) which phosphorylates smooth muscle proteins like myosin light chain
• Mechanism of action of protein kinase cascades


  1. Insulin, EGF, and IGF-1 have receptors with intrinsic protein kinase activities in their cytoplasmic domains

  2. Binding of the hormone induces autophosphorylation on tyrosine residues of the receptor, which stimulates the activity of many intracellular enzymes like protein kinases and lipid kinases

  3. Growth hormone and prolactin promote activation of cytoplasmic protein tyrosine kinases which phosphorylate one or more cytoplasmic proteins
• Insulin increases the activity of some enzymes by dephosphorylation (e.g. glycogen synthase) and decreases the activity of some enzymes by dephosphorylation (e.g. phosphorylase)
• Hormone


  Natural organic substance that regulates growth, metabolism and other functions of an organism
• Hormones


  • They are secreted in small amounts by endocrine glands and carried directly by the blood to act on target tissues
  • They can also act on adjacent cells (paracrine action) and on the cells in which they were synthesized (autocrine action) without entering the systemic circulation
• Target cell


  Any cell in which the hormone (ligand) binds to its receptor, whether or not a biochemical or physiologic response has yet been determined
• Characteristics of hormones


  • Present at very low concentrations in the blood (10-15 to 10-9 mol /L)
  • Initiate biologic effects by binding to specific receptors on or in target cells
  • Hormone-induced actions terminate when the effector dissociates from the receptor
  • Have short half-lifetime in blood due to rapid inactivation
• Hormone action


  • Alter plasma membrane permeability
  • Stimulate protein synthesis
  • Activate or deactivate enzyme systems
  • Induce secretory activity
  • Stimulate mitosis
• Classification of hormones


  • Based on chemical composition
  • Based on solubility properties
  • Based on location of receptors
  • Based on the nature of the signal used to mediate hormonal action within the cell

  
• Hormones derived from cholesterol

  Glucocorticoids, mineralocorticoids, androgens, estrogens, progestins, 1,25(OH)2-D3

  
• Amino acid derived hormones


  Catecholamines and thyroid hormones (tyrosine is the starting point)
• Polypeptide hormones


  Thyrotropin-releasing hormone (TRH), adrenocorticotropic hormone (ACTH), parathyroid hormone (PTH), growth hormone (GH), insulin
• Glycoprotein hormones


  Follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), chorionic gonadotropin (CG)
• Group I hormones


  Interact with intracellular receptors
• Group II hormones


  Interact with receptors located on the extracellular surface of the plasma membrane of target cells
• Mechanism of action of group I hormones


  1. Lipophilic hormone traverses plasma membrane and binds to cytoplasmic or nuclear receptor

  2. Hormone-receptor complex binds to specific region of DNA called hormone-receptor element (HRE) and activates or inactivates specific genes

  3. Results in changes in the amounts of specific proteins, which influence the metabolic processes
• Mechanism of action of group II hormones


  1. Use intracellular messengers (second messengers) such as cAMP, cGMP, Ca2+, phosphatidylinositides, protein kinase cascades

  2. Hormone binds to membrane receptor which is coupled to effector through a G-protein

  3. G-protein activation leads to production of second messenger which mediates the cellular effects
• 1. protein coupled receptors (GPCR)


  • Have seven α-helical hydrophobic plasma membrane-spanning domains
  • Bind to GTP-dependent regulatory G-proteins (Gs - stimulatory, Gi - inhibitory)
• Mechanism of action of cAMP as second messenger

  1. Hormone binds to GPCR, activating G-protein

  2. Activated G-protein activates adenylate cyclase enzyme

  3. Adenylate cyclase generates cAMP from ATP

  4. cAMP activates protein kinase A (PKA) which phosphorylates proteins and enzymes to cause cellular effects
• Termination of cAMP-mediated hormone actions

  1. Hydrolysis of cAMP by phosphodiesterases

  2. Dephosphorylation of phosphoproteins by phosphoprotein phosphatases
• Calcium and phosphoinositides as second messengers


  Used by hormones like muscarinic acetylcholine, angiotensin II, vasopressin, etc.
• IF 88nABnorC O A RAMPS Ade proteinkinaseA
• The interaction of the hormone with its receptor


  Results in the activation or inactivation of the adenyl cyclase
• GC A FIT glands save A
• Actions caused by hormones that increase cAMP concentration


  1. Hydrolysis of cAMP by phosphodiesterases

  2. Phosphoprotein phosphatases which cause dephosphorylation of phosphoproteins

  3. GDP in place of GTP to stop all mechanism
• Signals used by group II hormones


  • cAMP
  • Ca2+ and phosphatidylinositides
  • cGMP
  • Protein Kinase cascades