037 - Endocrinology Physiology] Receptor Pathways.pdf

Last edited: 9/28/2021 1. RECEPTOR PATHWAYS Endocrinology | Receptor Pathways Medical Editor: Ilia-Presiyan Georgiev OUT...

Last edited: 9/28/2021 1. RECEPTOR PATHWAYS Endocrinology | Receptor Pathways Medical Editor: Ilia-Presiyan Georgiev OUTLINE (2) The G protein is normally bound to GDP Binding of a peptide hormone (e.g., epinephrine or I) HORMONES oxytocin) changes the overall three-dimensional II) G PROTEIN-COUPLED RECEPTORS (GPCR) structure of the inside portion of the receptor III) STEROID HORMONR RECEPTORS o The receptor activates the G protein by removing the IV) INHIBITION V) APPENDIX GDP and adding on GTP VI) REVIEW QUESTIONS The activated G protein can move along the membrane VII) REFRENCES o Because it is a peripheral membrane protein ‘Off’ state – inactive receptor I) HORMONES o The G protein is bound to GDP (1) Peptide hormones ‘On’ state – active receptor o GDP is removed and GTP is added Oxytocin, insulin, glucagon, FSH, LH, GH, PTH, ADH etc. Water soluble o Have a hydrophilic amino acid o Do not precipitate Do not pass freely through the cell membrane (phospholipid bilayer) o Relatively big size o Charged o Water soluble proteins can’t penetrate phospholipid barrier Require a receptor on the cell membrane o Utilizes the 2nd Messenger Systems (Gs, Gq, Gi) (2) Steroid hormones Testosterone, estrogen, progesterone, aldosterone, cortisol, gonadocorticoids, etc. Figure 2 G protein-coupled receptor’s ‘on’ and ‘off’ states. Lipid soluble o Derived from cholesterol (B) GS PROTEIN-COUPLED RECEPTORS Pass through the phospholipid barrier Bind to receptors inside the cell (1) G stimulatory protein. The activated Gs protein goes to an effector enzyme on the cell membrane – Adenylate cyclase o The effector enzyme has a specific point of attachment for the Gs protein The effector enzyme becomes very active (2) Adenylate cyclase has a specific enzyme – GTPase o GTPase cuts the GTP and turns it into GDP (removes a phosphate)  G protein is turned off o Energy is produced and used to convert ATP to cAMP  cAMP activates protein kinase A (pkA) A kinase, by definition, is an enzyme that phosphorylates Figure 1 Peptide (blue) and steroid (red) hormones interacting with a cell. II) G PROTEIN-COUPLED RECEPTORS (GPCR) (1) Receptor structure Receptor with seven transmembrane helices o Structure protein passes through the membrane 7 times o A.k.a seven pass transmembrane receptors or ‘serpentine’ receptors Binding sites for ligands are found in extracellular Figure 3 Gs coupled-protein receptor pathway. regions or between helices. o Has an intracellular binding site for the G protein Receptor Pathways ENDOCRINE PHYSIOLOGY: Note #1. 1 of 3 (3) The activated pkA can phosphorylate multiple proteins which leads to different effects: o Regulation of membrane permeability for different ions  Phosphorylation of channel proteins on the cell membrane o Regulation of metabolic pathways (glycolysis)  Phosphorylation of enzymes o Increased production of new proteins (transcription)  Phosphorylation of transcription factor o Increased cell proliferation and DNA replication, etc. Figure 5 Gq protein-coupled receptor's pathway (Oxytocin). III) STEROID HORMONR RECEPTORS Can be intra cytosolic or intranuclear Normally are bound to heat shock protein (HSP) o ‘Off’ state When a steroid hormone (testosterone) goes through the cell membrane and binds to the receptor it displaces the HSP and activates the receptor o ‘On’ state The activated receptor binds to a specific gene sequence Figure 4 Effects of protein kinase A. – hormone response element (HRE) A plethora of effects is triggered: (C) GQ PROTEIN-COUPLED RECEPTORS o DNA replication  Stimulates cell proliferation (mitosis) (1) The activated Gq protein o Transcription followed by translation goes to an effector enzyme on the cell membrane –  Stimulates the synthesis of proteins that: Phospholipase C Control metabolism o The effector enzyme has a specific point of Control ion permeability attachment for the Gq protein Control protein synthesis o The effector enzyme becomes very active Control cell growth (2) Phospholipase C has a specific enzyme – GTPase o GTPase cuts the GTP and turns it into GDP  G protein is turned off o Energy is produced and used to cut a specific molecule that is found in the membrane - phosphatidylinositol biphosphate (PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3)  DAG activates a specific enzyme – protein kinase C (pkC) (3) pkC has the same function as pkA Phosphorylation of different proteins o Leads to activation or deactivation IP3 affects the smooth endoplasmic reticulum in most cells or the sarcoplasmic reticulum in muscle cells. o The reticulum has specific receptors for IP3 IP3 binds to the receptor to open a specific channel Figure 6 Steroid hormone receptor pathway. o Calcium (Ca++) leaves the reticulum and goes in the cytoplasm. IV) INHIBITION (4) Calcium (Ca++) binds to Calmodulin which then activate different types The enzyme phosphodiesterase (PDE) breaks down of kinases cAMP or Phospholipase C to prevent these pathways The activated kinases phosphorylate different proteins from continuously occurring. o e.g., myosin to initiate contractions This is the mechanism oxytocin uses to increase the calcium levels inside the cell in order to cause contractions Figure 7 Effects of phosphodiesterase. 2 of 3 ENDOCRINE PHYSIOLOGY: Note #1. Receptor Pathways  V) APPENDIX Locations of the “Off” “On” Examples Solubility Effectors receptors state state Peptide Oxytocin, insulin, glucagon, FSH, LH, Water On the cell GDP GTP Kinases hormones GH, PTH, ADH soluble membrane Testosterone, estrogen, Steroid Lipid In the cytosol or in Steroid progesterone, aldosterone, cortisol, HSP HRE hormones soluble the nucleus hormone gonadocorticoids a. Effector enzyme VI) REVIEW QUESTIONS b. Gene sequence Which hormone is peptide in nature? c. Peptide hormone a. Estrogen d. Channel transporter b. Glucagon c. Aldosterone Which enzyme activates the GPCR? d. Cortisol a. Protein Kinase C b. Adenylate Cyclase Which hormone is steroid in nature? c. Phosphodiesterase a. Oxytocin d. GTPase b. Growth hormone c. Insulin d. Testosterone VII) REFRENCES What is a typical property of peptide hormones? Le T, Bhushan V, Sochat M, Chavda Y, Zureick A. First Aid for a. Can bind to intranuclear receptors the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017 Marieb EN, Hoehn K. Anatomy & Physiology. Hoboken, NJ: b. Water soluble Pearson; 2020. c. Can freely pass through a phospholipid barrier Boron WF, Boulpaep EL. Medical Physiology.; 2017. d. Derived from cholesterol Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical; 2018 What is a typical property of steroid hormones? Hall JE, Hall ME. Guyton and Hall Textbook of Medical a. Lipid soluble Physiology. Philadelphia, PA: Elsevier; 2021. b. Large size c. Have a hydrophilic amino acid in its structure. d. Can bind to membrane receptors Which molecule is related to the ‘on’ state of peptide hormones? a. ATP b. HSP c. GDP d. GTP Which molecule is related to the ‘off’ state of steroid hormones? a. cAMP b. GDP c. HRE d. HSP Which enzymes activated in the GsPCR pathway? a. Protein Kinase C b. Adenylate Cyclase c. Phosphodiesterase d. Phospholipase C Which enzymes activated in the GqPCR pathway? a. Phosphodiesterase b. Adenylate Cyclase c. Protein Kinase A d. Phospholipase C What is hormone response element? Receptor Pathways ENDOCRINE PHYSIOLOGY: Note #1. 3 of 3