Hormone (Dr. Amel) (56-2024) PDF

Hormone. )65 ‫)الدفعة‬. Dr. Mohamed Khomsi Fb: ‫ محمد الخمسي‬.‫د‬ Oct / 2024  Introduction to Hormones Other Name: - Hormones are also Called: (1) Messenger...

Hormone. )65 ‫)الدفعة‬. Dr. Mohamed Khomsi Fb: ‫ محمد الخمسي‬.‫د‬ Oct / 2024  Introduction to Hormones Other Name: - Hormones are also Called: (1) Messenger (2) Ligand. Classical Definition: - Are Chemical Substances Produced by Endocrine (Ductless) Glands Directly to the Blood to Act on Another Tissue. Modern Definition: - Are Chemical Substances Synthesized by One Type of Cells & Transported to Act on Another Type of Cells. Concentration: - Hormones are Present in Very Low Concentrations in Extracellular Fluid (Blood). - They Range from 10–15 to 10–9 mol/L (Femto to Nanomolar Range). Biomedical Importance: - Hormones are Important for a Variety of Functions. (1) Regulation of Carbohydrate, Protein & Lipid Metabolism, (2) Cell Growth, (3) Immune Function, (4) Control Reproductive Function, (5) Central Nervous System Functions. Mechanism of Action: - Hormones Initiate their Biologic Effects by Binding to Hormone-Specific Receptor. - Hormones Act by (1) Altering Rates of Enzyme Mediated Reactions. (2) Control the Movement of Molecules Across the Plasma Membrane. (3) Regulating the Rate of Gene Expression (Protein Production). 1  Introduction to Hormones Chemistry: - Receptors are Proteins. Location: - There are 2 Locations of Receptors: Intracellular Receptors Extracellular Receptors Cytosolic or Nuclear Receptors Cell Membrane Receptors Directly Indirectly Form Hormone Receptor Complex Generate a Signal (2nd Messengers) Affect Gene Expression To Regulates Intracellular Enzyme e.g. e.g. LDH PDH Steroid, Thyroid Hormones Glucagon , Catecholamine Hormones Function: (1) Receptors Bind to a Specific Hormones. (2) Generate an Intracellular Signal (Receptor-Effector Coupling). Domain: - Receptors have at Least Two Functional Domains. Recognition Domain Signal Transduction Domain Generates a Signal that Couples Binds the Hormone Ligand Hormone to Intracellular Function Interaction: - The Interaction between Hormone & Receptor has the Following Features: (1) Specific (Selective). (2) Saturable. (3) Occur within Concentration Range of Expected Biologic Response. - Hormones are Displaceable by Agonist or Antagonist. 2  Introduction to Hormones Diversity of Endocrine System: - Hormones Are Synthesized in a Variety of Cellular Arrangements. (1) Some Hormones are Synthesized in Discrete Organs Designed Solely for this Specific Purpose. For Examples - Thyroid (Triiodothyronine), - Adrenal (Glucocorticoids & Mineralocorticoids), Pituitary (TSH, FSH, LH, GH, PRL, ACTH). (2) Some Hormones are Synthesized in Organs that Perform 2 Distinct but Closely Related Functions. For Example - Ovaries Produce Mature Oocytes & Estradiol & Progesterone. - Testes Produce Mature Spermatozoa & Testosterone. (3) Some Hormones are Synthesized by Specialized Cells Within Other Organs For Example - Small Intestine (Glucagon-Like Peptide). - Thyroid (Calcitonin). - Kidney (Angiotensin II). (4) Some Hormone are Synthesized by Parenchymal Cells of More than One Organ For Example - The Skin, Liver & Kidney are Required for Production of 1,25(OH)2-D3 (Calcitriol). 3  Classification to Hormones Classification Hormones are Classified According to: Classification Type of Hormone According to - Autocrine Hormones Distance of Action - Paracrine Hormones - Endocrine Hormones According to - Lipid-Derived Hormones Chemical Composition - Protein-Derived Hormones According to - Non-polar Hormones Solubility (Polarity) - Polar Hormones According - Intracellular Hormones Location of Receptor - Extracellular Hormones (Signal Used, Mechanism of Action) Hormones Distance of Chemical Receptor Polarity Action Nature Location - Autocrine - Lipid - Nonpolar - Intracellular - Paracrine - Protein - Polar - Extracellular - Endocrine 4  Classification of Hormones According to Distance of Action, Hormones are Classified into: (1) Autocrine, (2) Paracrine, (3) Endocrine. Autocrine Paracrine Endocrine Hormones Hormones Hormones Acts on Acts on Acts on Cell in Which they Synthesized Adjacent Cells Another Type of Cell Without Entering Without Entering Transported in the Systemic Circulation the Systemic Circulation Systemic Circulation (Blood) e.g. e.g. e.g. Eicosanoids Estrogen Most Hormones Prostaglandins (PG) Progesterone ** Most Hormones are Endocrine ** 5  Classification of Hormones According to Chemical Composition, Hormones are Classified into: (1) Lipid-Derived, (2) Protein-Derived. Lipid-Derived Hormones Protein-Derived Hormones Eicosanoids Catecholamines Calcitriol Thyroid Retinoic acid Serotonin Androgen Melatonin Testosterone TRH Estrogen ACTH Progesterone Insulin Cortisol Glucagon Aldosterone PTH GH LH FSH TSH CG ** Most Hormones are Peptides or Proteins ** TRH = Thyrotropin Releasing Hormone. ACTH = Adrenocorticotropic Hormone. PTH = Parathyroid Hormone. GH = Growth Hormone. LH = Luteinizing Hormone. FSH = Follicle-Stimulating Hormone. TSH = Thyroid-Stimulating Hormone. CG = Chorionic Gonadotropin. 6  Classification of Hormones - Lipid Hormones are Derived from: Fatty Acid, Cholesterol. - Protein Hormones are Derived from: Amino acid, Polypeptide, Glycoprotein. Lipid-Derived Hormones Protein-Derived Hormones Amino Acids: - Tyrosine: Fatty Acids: Catecholamines, Thyroid - Eicosanoids (PG). - Tryptophan: Serotonin, Melatonin Peptide, Polypeptide, Protein: TRH (3a.a Tripeptide) Cholesterol (Steroid Hormones): ACTH (39 a.a) Fat Soluble Vitamin: Insulin (51 a.a) Vitamin D & Vitamin A PTH (84 a.a) Sex Hormones: GH (191 a.a) Androgen, Testosterone, Estrogen, Progesterone Corticosteroids: Glycoproteins: Cortisol, Aldosterone - LH - FSH - TSH - CG - Vitamin D = Calcitriol = 1,25-Dihydroxycholecalciferol. - Vitamin A = Retinoids = Retinoic acid. - Cortisol = Glucocorticoids. - Aldosterone = Mineralocorticoids. - Catecholamines = Adrenaline, Noradrenaline, Dopamine. - Thyroids = T3, T4 (Thyroxine). 7  Classification of Hormones According to Polarity (Solubility), Hormones are Classified into: (1) Non-polar, (2) Polar. Group I Hormones Group II Hormones Non-polar Hormones Polar Hormones Hydrophobic Hormones Hydrophilic Hormones Water-Insoluble Hormones Water-Soluble Hormones Needs transporter in blood Doesn’t Need transporter in blood Has Long half-life Has Short half-life (Hours- Days) (Minutes) E.g. E.g. Lipid Derived Hormones Protein Derived hormones ** Most Hormones are Polar ** - Lipid Hormones are Transporter by Plasma Transport or Carrier Proteins. - Transporters Prolong Half-Life of Hormones. 8  Classification of Hormones According to Location of Receptor, Hormones are Classified into: (1) Intracellular, (2) Extracellular. Group I Hormones Group II Hormones Intracellular Hormones Extracellular Hormones Lipophilic Lipophobic Can Cross (Traverses) Cell Membrane Can't Cross (Traverses) Cell Membrane Encounters Intracellular Receptors Encounters Extracellular Receptors (Cytosolic or Nuclear Receptor) (Cell Surface Receptor) Doesn’t Need Seconds Messenger Needs Second Messenger Forms Hormone Receptor Complex Communicate with Intracellular Metabolic & Stimulates Genes Expression Processes through Second messengers The Intracellular Messenger (Mediators) is: The Intracellular Messenger (Mediators) is: Hormone Receptor Complex 2nd Messenger: cAMP, cGMP, IP3, DAG, Ca + Lipid Derived Hormones Protein Derived Hormones Except Eicosanoids Except Thyroid Hormones ** Most Hormones are Extracellular ** - All Lipid hormones have Intracellular receptors Except Eicosanoids. - All Protein hormones have Extracellular receptors Except Thyroids hormones. - Hormone Receptor Complex = Ligand Receptor Complex. - Hormone itself is the First Messenger. 9  Lipid Derived Hormones (Cholesterol Derivative Hormone) Vitamin D: - Vitamin D is Synthesized From a Cholesterol. - It is Activated to 1,25(OH)2-D3 (Calcitriol) by Series of Enzymatic Reactions. - Small Amount of Vitamin D is Synthesized from Precursor in Food. - Most of Vitamin D is Synthesized from Precursor in Malpighian Layer of Epidermis. - Vitamin D is Synthesized in the Skin. - Vitamin D is Synthesized from 7-Dehydrocholesterol. - Vitamin D is Synthesized by UV Light–Mediated, Non-Enzymatic Photolysis Reaction. - The Extent of this Conversion is Related Directly to the Intensity of the Exposure. - The Extent of this Conversion is Related Inversely to the Extent of Pigmentation of skin. - Vitamin D Binding Protein Transports D3 from Intestine or Skin to Liver. - Vitamin D3 Undergoes 25-Hydroxylation in Liver. - This Reaction occurs in the Endoplasmic Reticulum. - This Reaction Requires Molecular Oxygen, NADPH, Magnesium. - This Reaction Involves 2 Enzymes: (1) NADPH-Dependent Cytochrome P450 Reductase, (2) Cytochrome P450 Monooxygenase. - The 25(OH)2-D3 Enters the Circulation, it is the Major form of vitamin D in Plasma. - Vitamin D Binding Protein Transports 25(OH)2-D3 to the Kidney. - 25(OH)2-D3 is a Weak. - 25(OH)2-D3 Undergoes 1-Hydroxylation in Kidney. - This Reaction occurs in the Renal Proximal Convoluted Tubule of Kidney. - This Reaction occurs in the Mitochondria. - This Reaction Requires Molecular Oxygen, NADPH, Magnesium. - This Reaction Involves at least 3 Enzymes: (1) Renal Ferredoxin Reductase (Flavoprotein). (2) Renal Ferredoxin (Iron-Sulfur Protein). (3) Cytochrome P450. - This System Produces 1,25(OH)2-D3 (Calcitriol), - Which is the Most Potent of Vitamin D with Full Biologic Activity. - It Activates Biologic Processes in a Manner Similar to Steroid Hormones. 11  Amino Acid Derived Hormones - Catecholamines & Thyroid Hormones are Derived from the a.a Tyrosine. Catecholamines: Organ: - Synthesized by Adrenal Gland (Medulla). Cell: - Synthesized in the Chromaffin Cells. Type: - Amino Acid Derives Hormones. Precursor: - Synthesized from the Immediate Precursor Tyrosine. Include: They Include Three Amines: (1) Dopamine, (2) Noradrenaline (Norepinephrine), (3) Adrenaline (Epinephrine). - Adrenaline is The Major Product of the Adrenal Medulla. - Adrenaline Constitutes 80% of the Catecholamines in the medulla. - Adrenaline is Not Made in Extra-Medullary Tissue. - Most of Noradrenaline is Made in Situ by Nerve Ending (about 80% of the total). Synthesis: - The Conversion of Tyrosine to Epinephrine Requires Four Steps: (1) Ring Hydroxylation. (2) Decarboxylation. (3) Side Chain (β) Hydroxylation. (4) N-Methylation. - Catecholamines Are Synthesized in Final Form & Stored in Secretion Granules. Brain: - Catecholamines Cannot Cross the Blood Brain Barrier, - So the Brain Must them Synthesize them Locally. Medical Importance: - In Certain Central Nervous System Diseases (E.g. Parkinson Disease), - There is a Local Deficiency of Dopamine Synthesis. 11  Catecholamine Synthesis: Tyrosine Tyrosine Hydroxylase DOPA Dopa Decarboxylase Dopamine Dopamine β Hydroxylase Nor-Adrenaline N-Methyltransferase Adrenaline Tyrosine Hydroxylase - It Is Found Only in Tissues that Synthesize Catecholamines. - It is an Oxidoreductase, - It's Cofactor is Tetrahydropteridine (THP). - It is Rate-Limiting Enzyme (Step) for Catecholamine Biosynthesis. - It is Regulated by Feedback Inhibition by the Catecholamines, - Which Compete with the Enzyme for the Pteridine Cofactor. Dopa Decarboxylase - Is Present in All Tissues. - It is Requires Pyridoxal Phosphate (PLP). Dopamine β-Hydroxylase (DBH) - It Uses Ascorbate as an Electron Donor, - Copper at the Active Site, - DBH is in the Particulate Fraction of the Medullary cells, in the secretion granule. Phenylethanolamine-N-Methyltransferase (PNMT) - It is Found in the Epinephrine-Forming Cells of the Adrenal Medulla. - The Synthesis of PNMT is Induced by Glucocorticoid Hormones. - That Reach the Medulla via the Intra-adrenal Portal System. L-Dopa = L-dihydroxyphenylalanine. Dopamine = 3,4- Dihydroxyphenylethylamine. 12  Amino Acid Derived Hormones - Catecholamines & Thyroid Hormones are Derived from the a.a Tyrosine. Thyroid Hormones - The Synthesis of Thyroid Hormones Occurs in Seven Steps: (1) Iodide Trapping: - Iodide Enters the Thyroid by a Na-K ATPase Dependent Thyroidal I− Transporter, - This is an Energy-Dependent Process (2ry Active Transport). (2) Oxidation of Iodide: - In Thyroid Cell, Iodide is Oxidized to Active Iodine. - By Thyroperoxidase (Requires Hydrogen Peroxide (H2O2) as an Oxidizing Agent). - About 70% of the Iodide in Thyroglobulin Exists in the Inactive Precursors. (3) Iodination of Tyrosine: - Iodination of Tyrosine of Thyroglobulin (Tgb). - To Form Monoiodotyrosine (MIT) & Diiodotyrosine (DIT). - Once Tyrosine of Thyroglobulin is Iodinated, Iodine Does Not readily Leave Thyroid. (4) Coupling of T1 and T2: - Coupling of MIT & DIT to Form T3 (Tri-iodo-Thyronin) or 2 DIT to Form T4 (Tetra-iodo-thyronine). - This Step occurs Within the Thyroglobulin Molecule. - %99 of the Hormone Produced by the Thyroid Gland is T4. (5) Storage: - T3 and T4 are Stored by Thyroglobulin in the Colloid. - Several Weeks’ Supply of these Hormones Exist in the Normal Thyroid. (6) Secretion of Thyroid Hormones: - TSH Stimulates of the Thyroid Gland, - Colloid Reenters the Cell & there is Increase of Phagolysosome Activity. - Proteases & Peptidases Hydrolyze the Thyroglobulin into Amino acids, - Including T4 and T3, which are Discharged into the Extracellular Space. - The MIT & DIT that are not utilised are deiodinised by deiodinase & reutilization inside the cell. 13  Amino Acid Derived Hormones Thyroid Hormones (7) Conversion of T4 to T3: - In Peripheral Tissue, T4 is Converted to Active T3. - By De-iodination at 5' Position by a Deiodinase. - T3 is Biological Active Form. Half-Life: - T4: 4-7 days, - T3: 1 day. - Thyroglobulin is Synthesized by the Thyroid Follicular Cells. - Thyroglobulin is a Large Iodinated, Glycosylated Protein (Glycoprotein). - Thyroglobulin is Composed of 2 Large Subunits. - Thyroglobulin Contains 115 Tyrosine, Each of which is a Potential Site of Iodination. - T4 = Thyroxin. 14  Protein (Peptide) Derived Hormones Insulin Organ: - Synthesized by Pancreas. Cell: - Synthesized in the β islets (Cells) of Langerhans. Type: - Polypeptide Derived Hormone. Amino Acids: - 51 a.a. Chains: - Arranged in 2 Polypeptide Chains (Heterodimer). - A Chain (21 a.a). - B Chain (30 a.a). Disulfide Bridges: - 2 Interchain Bridges (Between A & B chains). - 1 Intrachain Bridge (Within A chain). Synthesis: - It is Synthesized as a Large Inactive Precursor. - Preproinsulin (108a.a) … Proinsulin (86a.a) … Insulin (51 a.a). - It is Synthesized by Sequentially Cleavage to Form Active Hormone & C-Peptide (Connecting-Peptide). - The Initial Cleavage is by a Trypsin-Like Enzyme. - Followed by Several Cleavages by a Carboxypeptidase-Like Enzyme. - The C-Peptide has Long Half-life in the Plasma & a Good Indicator of Insulin Production & Secretion. Degradation: - Insulin is Degraded by the Enzyme Insulinase (Present in Liver). Plasma Half-Life: - 6 Minutes. Storage: - Insulin is Stored in the Cytosol in Granules & Released by Exocytosis. 15  Protein (Peptide) Derived Hormones Insulin Regulation: - The Major Regulator of Insulin Secretion is Glucose. - An Increase in Blood Glucose level Stimulates Insulin Secretion. Function: - It is Important in Coordinating the Use of Fuels by Tissues. - It is an Anabolic Hormone. - It Increases: Glucose Uptake, Glycogen Synthesis, Lipid Synthesis & Protein Synthesis. - It Decreases: Gluconeogenesis, Glycogenlysis, Lipolysis 16  Protein (Peptide) Derived Hormones Glucagon Organ: - Synthesized by Pancreas. Cell: - Synthesized in the α islets (Cells) of Langerhans. Type: - Polypeptide Derived Hormone. Amino acids: - 29 a.a Chains - Arranged in 1 (Single) Polypeptide Chain. Synthesis: - It is Synthesized as a Large Inactive Precursor (Preproglucagon). - That is Converted to Glucagon. Degradation: - It is Inactivated in the Liver. Plasma Half-Life: - 5 Minutes. Regulation: - The Major Regulator of Glucagon Secretion is Glucose. - An Increase in Blood Glucose Level Inhibits Glucagon Secretion. Function: - It is important in Coordinating the use of Fuels by Tissues. - It is an Catabolic Hormone. - It Increases: Gluconeogenesis, Glycogenlysis, Lipolysis, Protein Degradation. 17  Intracellular Hormones - Intracellular Hormones have Cytosolic or Nuclear Receptors. - Receptor Activation occurs by at Least 2 Mechanisms. Hormones with Cytosolic Receptor Example: - Glucocorticoids (Cortisol). Mechanism of Action: - Hormone Diffuse Across the Plasma Membrane. - Hormone Encounters their Receptor in the Cytoplasm. - Hormone Forms a Hormone Receptor Complex. - This Results in a Conformational Change in the Receptor. - This Frees a Nuclear Localization Sequence. - Which Assist in the Translocation From Cytoplasm to Nucleus. - The Activated Receptor Moves into the Nucleus. - HRC Binds to a Specific DNA Sequence Called the Hormone Response Element (HRE). - Which Affects Rate of Transcription & Induces Formation of mRNA & Protein (Gene Expression). Hormones with Nuclear Receptor Example: - Retinoids (Vit A), Thyroid Hormones, Estrogen. Mechanism of Action: - Hormone Diffuse Across the Plasma Membrane. - Hormone Goes Directly into the Nucleus. - The Receptor is Already Bound to the HRE of DNA. - Which Affects Rate of Transcription & Induces Formation of mRNA & Protein (Gene Expression). The Hormone Response Gene for Thyroid Hormone is Called, Thyroid Hormone Response Element (TRE) 18  Extracellular Hormones - Extracellular Hormones have Receptors on the Surface of Cell Membrane. - These Hormones Use Intracellular 2nd Messengers. - These Second Messengers include: (1) Cyclic AMP(cAMP), (2) Calcium or Phosphatidylinositol (or both). (3) Cyclic GMP (cGMP), (4) Tyrosine Kinase Cascade. cAMP cGMP PI, IP3, DAG, Ca+ Tyrosine Kinase FSH LH Glucagon Prolactin ADH No Acetylcholine Insulin Catecholamines ANF Catecholamines Growth Hormone PTH ADH Erythropoietin Calcitonin ACTH TSH - ADH = Anti-Diuretic Hormone = Vasopressin Use cAMP & PI, Calcium - Catecholamines (α2 & β type Adrenergic) use cAMP - Catecholamines (α1-type Adrenergic) use PI, Calcium 19  Second Messengers Cyclic AMP (cAMP) Hormones: - FSH, LH, TSH, Glucagon, ADH Catecholamines, Calcitonin, PTH, ACTH Components: (1) Receptor, (2) G-Protein, (3) Effector. Receptor Seven α-Helical Domains Spanning Plasma Membrane Guanine Binding Protein G-Protein Hetero-Trimeric Composed of α, β, and γ subunits Effector Adenylyl Cyclase Initiation (Activation): - Hormone Binds to Receptor. - Leads to Conformation Change in Receptor. - Leads to Activation of G-Protein. - Leads to Exchange of GDP with GTP on α-Subunit. - Leads to Dissociation of α-Subunit from βγ. - GTP α Binds & Activates Adenyl Cyclase. - Adenyl Cyclase Converts ATP to cAMP. - cAMP Binds & Activates Protein Kinase A (PKA). - Kinase Phosphorylates the Enzymes. Termination (Inactivation): - This System Can be Terminated in a Number of Ways. - GTPase Hydrolyzes GTP, Which Inactivates G Protein & Adenyl Cyclase. - The αs Protein has Intrinsic GTPase Activity. - Phosphodiestrase (PDE) Hydrolyzes cAMP to 5' AMP. Medical Importance: - Cholera Toxin Catalyzes ADP Ribosylation of α Subunit. - This Modification Disrupts the Intrinsic GTPase Activity; - Causing Irreversible Activation of Adenyl Cyclase & Increased cAMP in Intestinal cells. - Leading to Increase in Secretion of Water & Cl Lead to Diarrhea & Sever Dehydration. 21  Second Messengers Phosphatidylinositol (IP3, DAG, Calcium) Hormones: - Acetylcholine, Catecholamine, ADH. Components: (1) Receptor, (2) G-Protein, (3) Effector. Receptor Seven α-Helical Domains Spanning Plasma Membrane Gq Isoforms G-Protein Effector Phospholipase C Initiation (Activation): - Hormone Binds to Receptor. - Leads to Conformation Change in Receptor. - Leads to Activation of G-Protein. - Leads to Exchange of GDP with GTP on α-Subunit. - Leads to Dissociation of α-Subunit from βγ. - GTP α Binds & Activates Phospholipase C. - Phospholipase C Hydrolyzes Phosphatidylinositol 4,5- bisphosphate to IP3 & DAG. - IP3, Binds to Receptor on Endoplasmic Reticulum to Releases Ca2+ from Intracellular Storage Sites. - The Activation of G-proteins Can also have a Direct Action on Ca 2+ Channels. - Elevations (Increase) of Cytosolic Ca 2+ Activates Ca2+ Calmodulin. - Active Calmodulin Activates Protein Kinase C (PKC). - DAG is itself Capable of Activating Protein Kinase C (PKC), - Kinase Phosphorylates the Enzymes. Calmodulin: - Calcium Modulated Protein. - Has 4 Binding Sites for Calcium. - IP3 = Inisitol Triphosphaste. - DAG = 1,2-Diacylglecerol. - Protein Kinase C = Ca-Calmodulin-Dependent Protein Kinase. Calcium, G-protein - Coupled Phosphatidyl inositol Ca Pathway 21  Second Messengers Cyclic GMP (cGMP): Hormones: - Atrial Natriuretic Factor (ANF), Nitric Oxide(NO). Components: (1) Receptor, (2) Effector. - The Effector is Guanyl Cyclase. - Guanyl Cyclase can be Membrane-Bound or Soluble. ANF Initiation (Activation): - Atriopeptins: Like Atrial Natriuretic Factor (ANF). - Are a Peptides Produced by Cardiac Atrial Tissues. - They Cause to Natriuresis, Diuresis, Vasodilation. - ANF Activates the Membrane-Bound Guanyl Cyclase. - Guanyl Cyclase Convert GTP to cGMP. - This Results in an Increase of cGMP. - cGMP Activates Protein Kinase G (PKG). NO Initiation (Activation): - Nitro-Compounds Like Nitric Oxide (NO), Nitroglycerin, Nitroprusside - They Cause Relaxation of Smooth Muscle & Vasodilation (Potent Vasodilators). - NO Activates Soluble Guanyl Cyclase. - Guanyl Cyclase Convert GTP to cGMP. - This Results in an Increase of cGMP. - cGMP Activates Protein Kinase G (PKG). - Which Phosphorylates a Number of Smooth Muscle Proteins. Termination (Inactivation): - Phosphodiestrase (PDE) Hydrolyzes cGMP to 5' AMP. Atrial Natriuretic Factor (ANF)Atrial Natriuretic Peptide (ANP) - Protein Kinase (PKG) = cGMP Dependent Kinase. 22  Second Messengers Tyrosine Kinase Cascade Hormones: - Insulin, GH, Prolactin & Erythropoietin. Components: (1) Receptor, (2) Effector. - The Effector is Tyrosine Kinase. - Tyrosine Kinas can be Membrane-Bound or Soluble. Insulin Initiation (Activation): - Insulin Acts by Binding to a Plasma Membrane Receptor. - Insulin Receptor is Heterotetramer. - It is Composed of 2 Copies of 2 Different Protein Subunits (α2β2) Linked by DSBs. - Insulin Binds to the Extracellular α Subunits. - β Subunit Spans Membrane & Transduces the Signal. - Through the Tyrosine Protein kinase Domain Located in the Cytoplasmic Portion β Subunit. - Leading to Auto-phosphorylation of the β Subunit. - This Event, in turn, Phosphorylates Insulin Receptor Substrates (IRS). - Which Affect Gene Expression, Cell Metabolism & Growth. - The Actions of Insulin are Terminated by Dephosphorylation. Growth Hormone & Prolactin Initiation (Activation): - GH Receptor & Prolactin (PRL) Receptors Do Not Contain Intrinsic Kinase Activity. - Ligand Binding to these receptors, - This Results in Activation of Cytoplasmic Tyrosine Kinases. - These Kinases Phosphorylate One or More Cytoplasmic Proteins. cGMP & PI,Calcium Use: - G-protein–Coupled Receptors (GPCRs). - Receptor–G-protein Effector System. 23