Biochemistry-Block-2.2-Hormones-part-2.pdf

BIOCHEMISTRY | BLOCK 2.2 Hormones (Hormone Action and Signal Transduction) Dr. Celina Vilches | 9/15/2022 | 9:30-11:30 AM Transcribed by: Pedro, Rodriguez, Samaniego, Samillano OUTLINE...

BIOCHEMISTRY | BLOCK 2.2 Hormones (Hormone Action and Signal Transduction) Dr. Celina Vilches | 9/15/2022 | 9:30-11:30 AM Transcribed by: Pedro, Rodriguez, Samaniego, Samillano OUTLINE CLASSES OF HORMONES 1. Signal Transduction Group I 2. Classes of Hormones - lipid soluble (lipophilic) a. Group I - cause signal transduction by passing through the b. Group II cell membrane and binding to their intracellular 3. Classification of Hormones based on receptor forming an hormone receptor complex type of receptor which will then affect gene transcription and to a. G protein coupled receptors minimal degree influencing the opening and b. Catalytic receptor closing of transporter channels. 4. Classification of Hormones based on type of secondary messenger Group II a. cAMP - water soluble (hydrophilic) b. cGMP - causes signal transduction by binding to its c. Calcium membrane receptor and using a second d. Kinase or phosphatase cascade messenger to create different signals intracellularly to modulate gene transcription, influence transporter channels, affect protein SIGNAL TRANSDUCTION translocation and modification. Signal transduction at the cellular level refers to the movement of signals from outside the cell to inside. Signals from the outside enters into the cell and cause cascade of events or the signal can be amplified through amplifying enzyme resulting to several changes within the cell. 1 References:  CLASSIFICATION OF HORMONES BASED ON MECHANISM OF WATER-SOLUBLE HORMONES THE TYPE OF RECEPTOR Membrane receptors Utilizes 2nd messenger systems which activate protein kinase o cAMP o cGMP o Calcium or Phosphatidylinositols or both o Kinase or Phosphatase Cascade Signal Transduction of Group II Hormones Components Receptor Effector enzyme Second messenger Protein kinases Membrane Receptors Membrane receptors can be divided into two groups, the receptors that is coupled to a G protein inside the cell are called G Protein coupled receptors and the receptors that possess catalytic enzymes within its structure or Hormones that bind with intracellular receptors uses enzymatic receptors to stimulate their Hormones that form complexes with the surface or target cells membrane receptors. o cAMP, cGMP, Calcium, phosphatidylinositol, kinase and phosphate cascades are further classified into the different type of second messenger they employ to amplify their signals 2 References: G proteins 4. It then activates the effector enzyme, in the case - ability to bind with Guanosine triphosphate of Gs its adenylyl cyclase which in turn catalyzes (GTP) the formation of cAMP from ATP - capable of hydrolyzing GTP to GDP. 5. When the hormone dissociates from its - G proteins are attached to the cell membrane receptor, the GTP at the alpha subunit is - Represent the largest family of cell surface hydrolyzed to GDP, the adenylyl cyclase is receptors in humans inactivated and the alpha subunit recombines with the beta and gamma subunits to form an Two categories of G proteins: inactive G protein Heterotrimeric G proteins - have 3 subunits (, , ) - coupled to a receptor that has 7 membrane spanning regions - not capable of catalysis - require another messenger to carry out the message in the target organ The Ras superfamily of G Proteins - Monomers resemble a sub unit of the heterotrimeric G-protein - coupled with receptors that has catalytic activity - the receptors that are capable of catalysis and don’t require the second messengers. There are several types of G proteins, mostly because of the characteristics of the alpha sub-unit. Certain G alpha subunits interacts with certain enzyme. The Gs which interacts with the effector enzyme adenylyl cyclase, G alpha subunits are Mechanism of Signal Transduction: distinguished from each other by their subscripts s, I 1. binding of the hormone to its receptor and q. G alpha i is inhibitory thus inhibiting adenylyl 2. the coupled receptor will undergo a formational cyclase, a G alpha olfactory is stimulatory and a Gq change and interact with the G protein. It which acts through phospholipase C. becomes activated and the alpha subunit releases GDP and binds with GTP The identity of the enzyme determines which second 3. The alpha subunit becomes activated and messenger will be produced. dissociate itself from the beta and gamma subunits. 3 References:  Cytosolic IP3 binds to sites on the endoplasmic reticulum, opening Ca2+ channels and allowing stored Ca2+ to flood the cytosol. There it activates numerous enzymes, many by activating their calmodulin or calmodulin-like subunits. DAG has 2 roles: o it binds and activates protein kinase C (PKC) o opens Ca2+ channels in the plasma When adenylyl cyclase is activated the second membrane, reinforcing the effect of IP3. messenger formed is cAMP, when guanylyl cycles is Like PKA, PKC phosphorylates serine and activated then cGMP is formed and when Phospholipase threonine residues of many proteins, thus C is activated Phosphotidylinositol, Diacyl glycerol and modulating their catalytic activity. Calcium ion is formed. Effector Enzyme/Amplifying Enzymes Adenylyl Cyclase – catalyzes the formation of cAMP from ATP Phospholipase C – IP3, DAG and Calcium Guanylyl cyclase – cGMP G-alpha q subunit o activates the effector or amplifying enzyme which is phospholipase C found in the cell membrane o acts on the membrane phospholipid phosphatidylinositol 4,5-bisphosphate SECOND MESSENGER – INTRACELLULAR SIGNAL (PIP2) to produce 2 messengers: cAMP ▪ IP3 - soluble in the cytosol, and − In eukaryotic cells, cAMP binds to a protein ▪ DAG - remains in the membrane kinase called protein kinase A (PKA) phase. 4 References: Termination of Activities of Hormones that uses cAMP Viagra (Sildenafil) as second messenger − Inhibits cGMP phosphodiesterase → increases Hydrolysis of cAMP to 5’ -AMP by cGMP → Vasodilation Phosphodiesterase − Potent vasodilator Dephosphorylation of phosphoprotein by phosphoprotein phosphatases Calcium Metabolism of Calcium *Methylated xanthine derivatives such as caffeine inhibits phosphodiesterase thus increasing the level of - ECF Ca Conc. = 55mol/L cyclic AMP. - ICF free Ca Conc. = 0.05-10umol/L − 3 mechanisms that controls Ca conc. cGMP ⮚ Na/Ca pump which pumps Ca out of the cell - High capacity but low affinity − Activates cGMP-dependent protein kinase − Ca/proton ATPase dependent pump extrudes Ca (PKG) o Phosphorylation of smooth muscle in exchange for H proteins - High affinity for Ca but low capacity o Involved in relaxation of smooth - Responsible fpr fine tuning of cytosolic muscle and vasodilation Ca − cGMP derived from GTP by catalysis of − Ca ATPase pumps Ca from cytosol to the lumen enzyme Guanylyl cyclase of the ER Guanylyl Cyclase 2 forms of Guanylyl cyclase 3 ways to change Calcium Concentration Intracellularly − Membrane bound form Hormones binds with receptors that actually − Soluble form calcium channels or open calcium channels - Causes influx of calcium Compounds that activate membrane bound guanylyl - Activation of phospholipase C which cyclase causes the formation of IP3 and DAG Atriopeptins (ex: Atrial Natriuretic Factor) − Hormones which modulate the membrane - Produced in the cardiac atrial tissue - Increases cGMP potential at the plasma membrane - Effects (natriuresis, diuresis, - Indirectly cause inc. Ca influx causing vasodilation, inhibition of aldosterone membrane depolarization the it opens secretion) voltage-gated Ca channel Compounds that bind with soluble form of Guanylyl − Hormones can cause Calcium be mobilized from cyclase the ER and from the mitochondria - Causes smooth muscle relaxation → potent vasodilators - Nitroprusside, Nitroglycerin, Nitric Oxide, Sodium Nitrite, Sodium azide Termination of Activities of Hormones that uses cGMP as second messenger Hydrolysis of cGMP which is catalyzed by cGMP phosphodiesterase 5 References:  2 types of signaling - Send signals through receptors that have intrinsic tyrosine kinase activity resulting to Protein Kinase Cascade - Send sign through non receptor tyrosine kinase Receptor single membrane spanning protein Ras G Proteins Homologous to the alpha subunits of heterotrimetric G proteins Do not regulate membrane-bound enzyme or induce the production of second messenger Activated by GTP Initiates a cytoplasmic phosphorylation cascade that terminates with activation of gene Protein Kinase Cascade transcription Features of the hormones action - Regulates cell proliferation Involved in growth control; differentiation and inflammation Mutation in Ras can cause unregulated cell division and Kinases preferentially phosphorylate malignancy tyrosine residue Phosphorylation of tyrosine residue will Calmodulin initiate a cascade that may involve Calcium dependent regulatory protein several protein kinases Homologous to Troponin C Epidermal Growth Factors, Insulin, Activated when Calcium binds to its 4 binding Insulin like Growth Factor sites - Activation of enzymes and ion channels - Regulates the activity of structural elements in cell - Actin-myosin complex of smooth muscle - Microfilament-mediated processes - Ex. Cell motility, endocytosis Catalytic Receptor These are receptors that does not depend on second messengers to activate protein kinase 6 References: Signaling of Nonreceptor tyrosine kinases Ligand Binding Domain Used by hormones, such as growth hormone, Gene regulatory domain prolactin, erythropoietin, and the cytokines Inhibitors Initiates their action by activating a tyrosine kinase Is not an integral part of the hormone receptor The cytoplasmic domains are noncovalently associated with the cytoplasmic tyrosine kinase proteins JAK (Janus Kinase Family) One of the best characterized nonreceptor tyrosine kinases Nuclear Receptors The receptor is bound to the HRE found in the DNA Inactive because it exists in with a corepressor H-R-HRE will result in the dissociation of the corepressor Signal Transduction of Lipid Soluble Hormones Diffuses through the cell membrane Binds to their respective receptors inside the cell HRE Requires activation reaction Resemble enhancer elements 2 types Not strictly dependent on position and Cytoplasmic location or orientation in order to exert Nuclear its action Cytoplasmic Receptors Bind the hormone-receptor complex more avidly 3 major functional domains than surrounding DNA DNA binding Domain Some HRE have extensive sequence similarity - Contains the nuclear localization sequence 7 References: