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MECHANISM OF ACTION OF HORMONES

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MECHANISM OF ACTION OF HORMONES

  1. 1.  The hormone is “substances released from ductless or endocrine glands directly to the blood”.  A more modern definition of a hormone is that it is synthesized by one type of cells & transported through blood to act on another type of cells.
  2. 2.  Signal Transduction through G protein:  Action is through G protein coupled receptors (GPCR).  Action of several hormones is effected through this mechanism.  The GPCRs are transmembrane proteins with 7 helical segments spanning the membrane.
  3. 3.  When any ligand binds, GPCRs activate heterotrimeric GTP binding regulatory proteins (G-proteins).  The G-protein will interact with effector proteins which may be enzymes or ion channel proteins, which result in the desired effect.  Different types of G proteins are present in the cells that are coupled with different receptors & activating different effector proteins.
  4. 4.  The extracellular messenger, the hormone (H) combines with the specific receptor (R) on the plasma membrane.  The H-R complex activates the regulatory component of the protein designated as G-protein or nucleotide regulatory protein.  G proteins – they can bind GTP & GDP.  The G-protein is a membrane protein consisting of α, β and γ subunits.
  5. 5.  When the hormone receptor complex is formed, the activated receptor stimulates the G protein, which carries the excitation signal to adenylate cyclase.  The hormone is not passed through the membrane; but only the signal is passed; hence this mechanism is called signal transduction.  The adenyl cyclase is embedded in the plasma membrane.
  6. 6.  When activated, GTP binds & β-γ subunits dissociate from the α subunit.  Adenylate cyclase is activated by Gα – GTP.  The binding of hormone to the receptor triggers a configurational change in the G protein which induces the release of bound GDP & allows GTP to bind.  The hormone has an amplified response, since several molecules of Gα – GTP are formed.
  7. 7.  The active Gα – GTP is immediately inactivated by GTPase.  The Gα – GDP form is inactive.  The activation is switched off when the GTP is hydrolysed to GDP by the GTPase activity of the α subunit.  The α subunit, which is bound to GDP, can re- associate with β and γ subunits.  The GTP-GDP exchange rate decides the activity of adenyl cyclase.
  8. 8.  Adenyl cyclase or adenylate cyclase converts ATP to cAMP (3',5'-cyclic AMP) & phosphodiesterase hydrolyses cAMP to 5' AMP.  Cyclic AMP is a second messenger produced in the cell in response to activation of adenylate cyclase by active G protein.  During hormonal stimulation, cyclic AMP level in the cell increases several times.
  9. 9.  Acts as second messenger in the cell.  Regulates glycogen metabolism – increased cAMP produces breakdown of glycogen (glycogenolysis).  Regulates TGL metabolism – increased cAMP produces lipolysis (breakdown of TGL).  cAMP stimulates protein kinases.  cAMP modulates transcription & translation.
  10. 10.  cAMP involved in steroid biosynthesis.  cAMP regulates permeability of cell membranes to water, Na+, K+ & calcium.  Involved in regulation insulin secretion, catecholamine & melatonin synthesis.  Histamine increases cAMP, which increases gastric secretion.
  11. 11.  cGMP involved in phosphorylation of proteins. E.g. acetyl choline in smooth muscle.  Role in vasodilation:  Nitroglycerine, cerine, sodium nitrite etc. causes smooth muscle relaxation & vasodilation by increasing cGMP.  Role in action of neurotransmitters:  GABA has been claimed to change cGMP levels in cerebral tissues.
  12. 12.  Role in prostaglandin synthesis:  PG-F2 require cGMP for its action.  Role in insulin actions:  Insulin action in some tissues is mediated through cGMP, which activates protein kinases.  Role in vasodilation produced by nitric oxide:  NO produces vasodilation & lowering BP by increasing cGMP.
  13. 13.  Calcium is intracellular regulator of cell function.  Intracellular calcium level is low than extracellular calcium.  3 types of calcium transport systems:  Voltage gated calcium channel.  Sodium/calcium antiport transporter.  Calcium transporting ATPase.
  14. 14.  This type of signal transduction is phospholipase C that hydrolyses phosphatidyl inositol to 1,4,5-Inositol triphosphate (IP3) & Diacyl Glycerol (DAG) that act as second messengers.  PIP3 (Phosphatidyl Inositol 3,4,5- phosphate) is another second messenger produced by the action of a phosphoinositide kinase.
  15. 15.  The phospholipase C may be activated either by G proteins or calcium ions.  DAG can also be generated by the action of phospholipase D that produces phosphatidic acid which is hydrolyzed to DAG.
  16. 16.  The steroid & thyroid hormones are included in this group.  They diffuse through plasma membrane & bind to the receptors in the cytoplasm.  The hormone receptor (HR) complex is formed in the cytoplasm.
  17. 17.  The complex is then translocated to the nucleus.  Steroid hormone receptor proteins have a molecular weight of about 80-100 kD.  Each monomer binds to a single steroid molecule at a hydrophobic site, but on binding to genes they dimerise.
  18. 18.  The HR complex binds to HRE (hormone responsive element).  HRE increase transcriptional activity.  Newly formed mRNA is translated to specific protein, which brings metabolic effects.  Steroid hormones influence gene expression & rate of transcription is also increased.
  19. 19.  Textbook of Biochemistry – DM Vasudevan  Textbook of Biochemistry – U Satyanarayana  Textbook of Biochemistry – MN Chatterjea

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