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Endo 2   kevin Endo 2 kevin Presentation Transcript

  • Mechanism ofHormoneAction
  • Mechanism of HormoneAction Each hormone exerts a characteristic effects on the target organ by acting on the cells of the organ  But same chemical category of hormone have similar mechanisms of action  Involves a. Location of cellular receptor proteins b. Events occurring in the target cells after the hormone has combined w/ its receptor protein
  • Mechanism of HormoneAction Hormones are delivered by blood to every cell in the body  But! Only target cells are able to respond to these hormones.  Target cells must have specific receptor proteins that is SPECIFIC Hormonesbind with a high affinity and low capacity View slide
  • Location of Hormone’sReceptor Protein Depends on the chemical nature of hormone  Lipid-soluble hormone receptor are located within the target cells  Because they can pass through cell membrane and enter target cell  Water-soluble hormone receptor are located outside the target cells  Because they can’t pass through cell membrane  Therefore they need the activation of 2nd messengers within the cell for hormone action View slide
  • Lipid-soluble Hormone Action Hormones includes thyroid and steroid hormones + nitric acid Attached to plasma carrier proteins then dissociate to pass thru lipid component of plasma membrane to enter cell where the receptor proteins are located
  • Lipid-soluble Hormone Action Receptorare called “nuclear hormone receptors”  Because they func. w/in the nucleus to activate genetic transcription (production of mRNA)  Thus func. as transcription factors  Has two regions or domains a. ligand-binding domain/hormone-binding domain b. DNA-binding domain
  • Nuclear Hormone Receptors With two families: a. Steroid family b. Thyroid Hormone family – includes receptors for active form of Vit. D and for retinoic acid that play important roles in the regulation of cell function and organ physiology  Receptors for unknown hormone ligands are called “orphan receptors”
  • Mechanism of SteroidHormone Action1. Hormone-receptor binding(in cytoplasm)2. Translocation to nucleus3. DNA-binding domain binds to specific hormone-response element of DNA • Hormone response element of DNA have two half-sites, each 6 nucleotide bases long, separated by 3-nucleotide spacer segment.
  • Mechanism of SteroidHormone Action Onesteroid receptor binds to one half-site and another to the other half-site  Thus called “dimerization”  “Monodimer” due to same receptor unit binds to the DNA hormone-response element
  • Ligand-bindingDimerization of receptors domain Steroid DNA-binding hormone domain Half-sites DNA Genetic transcription Hormone-response element RNA
  • Mechanism of ThyroidHormone Action Major hormone secreted is thyroxine or tetraiodothyrinine(T4) Small amount of triiodothyronine (T3)  Travels through blood and attached to carrier proteins primarily “thyroxine-binding globulin” or TBG which has higher affinity to T4 than T3
  • Mechanism of ThyroidHormone Action Approximately 99.96% of thyroxine in the blood is attached to carrier proteins in the plasma • The rest are free Only thyroxine and T3 can enter target cells Protein bound thyroxine serves as reservoir of the hormone in the blood Once free thyroxine enter cytoplasm, it is enzymatically converted to T3 • T3 is the one active in cytoplasm
  • Mechanism of ThyroidHormone Action Inactive receptor proteins for T3 are located in the nucleus Incapable of binding to DNA and stimulate transcription unless bind with T3 T3 enters cell from plasma or may be produced in the cell by converting T4 Needs a binding protein to enter nucleus
  • Mechanism of ThyroidHormone Action Difference to steriod:  Binds with non-specific binding protein in the cytoplasm  nuclear receptor is heterodimer(diff. receptor proteins attached to the half-sites)
  • Water-soluble Hormone Action Includes catecholamines (epi and norepinephrine), polypeptides and glycoproteins Cannot pass through lipid barrier of target cell Some may enter through “pinocytosis” but mostly acts on the outer surface of the target cell and therefore can be mediated by other molecules Uses 2nd messenger to exert their effects
  • Second-messenger SystemsA. Adenylate Cyclase-Cyclic AMP (cAMP) Second Messenger SystemB. Phospholipase C-Ca2+ Second- Messenger SystemC. Tyrosine Kinase Second-Messenger System
  • Adenylate Cyclase-CyclicAMP(cAMP) Second MessengerSystem For activation of adenylate cyclase First known and understood “second messenger” Responsible for b-adrenergic effects of epi and norepinephrine
  • Cyclic AdenosineMonophosphate Hormone(water-soluble) binds to receptor protein results to dissociation of subunit from the G-protein G-protein subunits moves thru membrane to bind and activates adenylate cyclase as catalyst  ATP cAMP + Ppi Intracellular concentration of this increases
  • Cyclic AdenosineMonophosphate Activates protein kinase  Inactivated form:  Catalytic subunit and inhibitory subunit  Becomes active once cAMP binds to inhibitory and dissociate from catalytic subunit insummary, the hormone causes an increase in protein kinase enzyme activity within its target cells
  • Cyclic AdenosineMonophosphate Activeprotein kinase catalyzes phosphorylation of diff. proteins in the cell causing some enzymes to be activated and others to be inactivated cAMP must be rapidly inactivated by phosphosdiesterase to function effectively
  • Phospholipase C-Ca2+Second Messenger System Ca pumps in the plasma membrane and endoplasmic reticulum keeps Ca concentration very low in the cytoplasm The steep concentration gradient for Ca that results allows various stimuli to evoke a rapid diffusion of Ca into the cytoplasm that serves as a signal in diff. control systems The entry of the Ca thru voltage-regulated Ca channels in the plasma membrane serves as a signal for the release of neurotransmitters
  • Phospholipase C-Ca2+Second Messenger System When epinephrine stimulates target organ, it must first bind to andrenergic receptor proteins in the membrane 2 types of adrenergic receptors: a. Alpha b. Beta  Alpha adrenergic receptors by epinephrine activates the target cell via the Ca second-messenger system
  • Phospholipase C-Ca2+Second Messenger System G-proteinintermediate enables binding of epinephrine to alpha-adrenergic receptor and the binding activates phospholipase C • Substrate is split by an active enzyme into inositol triphosphate (IP3) and diacylglycerol (DAG) that both acts as second messengers but IP3 is better understood
  • Phospholipase C-Ca2+Second Messenger System IP3leaves the plasma membrane and diffuses thru the cytoplasm to the endoplasmic reticulum • Membrane of ER has receptor for IP3 so the message of hormone is carried by IP3 from cytoplasm to ER  Thebinding of IP3 to receptor causes specific Ca channels to open.
  • Phospholipase C-Ca2+Second Messenger System Results to rapid and transient rise of cytoplasmic Ca concentration Ca that enters the cytoplasm binds to a protein called “calmodulin” Activated calmodulin then activates other specific protein kinase enzymes that modify actions of other enzymes in the cell
  • Tyrosine KinaseSecond-Messenger System Insulin promotes glucose and amino acid transport and stimulates glycogen, fat and protein synthesis Primary target organs are liver, skeletal muscles and adipose tissue Insulin’s mechanism of action is same with growth factors’
  • Insulin Mechanism of Action “Tyrosine kinase” is the enzyme that serves as receptor protein for insulin and GF  Specifically adds phosphate groups to amino acid tyrosine with in the protein  With two units(dimer) when binds to insulin forming active tyrosine kinase enzyme  Each unit have ligand-binding site and an enzymatic site  Ligand binding site-outside site that binds with insulin  Enzymatic site-part that spans the plasma membrane
  • Insulin Mechanism of Action Enzymatic site activates only after binding of insulin to ligand-binding site and causes dimerization of the receptor One unit then phosphorylates the other - “autophosphorylation” Signaling molecules are proteins phosphorylated by the activated tyrosine kinase receptor  Activates second messenger systems
  • Insulin Mechanism of Action The complex reactions enables the insulin to regulate the metabolism of its target cells.  Example: • binding of insulin to its receptor indirectly causes the activation of “glycogen synthetase”  Enzyme in liver and skeletal muscles that catalyzes the production of glycogen