Molecular Endocrine: Signals Transduction and Receptors Lecture 10 PDF

Molecular Endocrine: Signals Transduction and Receptors ● Endocrine System- Glands and tissues secrete hormones, or chemicals that affect other glands/tissues. ➢ Hormones target sites far away from them - Hormones, are ligands and bind to receptors specific to them - Receptors- Cell membrane or with...

Molecular Endocrine: Signals Transduction and Receptors ● Endocrine System- Glands and tissues secrete hormones, or chemicals that affect other glands/tissues. ➢ Hormones target sites far away from them - Hormones, are ligands and bind to receptors specific to them - Receptors- Cell membrane or within cell ➢ Homeostasis Maintenance- By cellular metabolism, growth, and development - Cooperation between endocrine and nervous systems Endocrine Nervous Hormones into blood Nerve impulses Slow response Fast response Prolonged response Shorter response ● Hormone Classes ➢ Peptides and Proteins- Glycoproteins ➢ Amino Acid Derivatives- Catecholamines/ Thyroid Hormones/ Melatonin ➢ Steroids- Sex steroids/ Corticosteroids ● Hormone Classification ➢ Lipophilic- Nonpolar and Fat soluble, pass through membrane - Steroid and thyroid hormones - Travel to transport proteins in blood. Dissociate from carrier at target cells - Bind to intracellular receptors or nucleus - Acts over short time - Hormone receptor complex- Binds to hormone response elements in DNA - Regulates gene expression ➢ Hydrophilic- Polar and Water soluble - Hormones besides steroid and thyroid - Freely soluble in blood - Bind to extracellular receptors - Longer active period ● Characteristics of Hydrophilic Hormones - Hormone Types- Peptide/Protein/Glycoprotein/Catecholamine - Cannot cross cell membrane- Too polar/large - Bind to cell membrane receptors - Initiate cell transduction pathways - Protein Kinase Activation ➔ Activate or deactivates intracellular proteins by phosphorylation - Second Messenger Production ● Hormone Homeostasis Controlled By Molecular Endocrine: Signals Transduction and Receptors ➢ Negative feedback - By condition it regulates - Blood concentration of hormone it is producing - Example of negative feedback- As blood glucose rises the pancreas will secrete insulin, which will cause the liver to store glucose and the removal of glucose from the blood. Insulin production is inhibited and the pancreas will stop secreting insulin from this process. ➔ Action of other hormones- I.e. insulin and glucagon - Blood Concentration of a substance stimulates endocrine gland to secrete its hormone ➔ Ex of long lasting response- Parathyroid gland secretes hormones when Ca2+ level goes below normal. Osteoclasts will respond to the hormone by slowly releasing Ca2+ from bone. - Hormone Release Regulation- Antagonistic Hormones, Insulin offset by glucagon- Insulin lowers blood glucose while glucagon raises it - Aldosterone secretion is regulated by the renin-angiotensin-aldosterone (RAA) pathway ➔ RAAS pathway: Increase in blood pressure by causing blood vessels to constrict (decrease in diameter) with angiotensin 2. 1. Blood pressure drops 2. The sympathetic nervous system stimulates the kidney’s juxtaglomerular cells to release renin. 3. Renin enters into circulation and activates angiotensinogen from the liver. 4. Because of renin, it will transform from angiotensinogen to angiotensin 1. 5. Angiotensin-converting enzyme (ACE) (on lung and kidney epithelial cells) converts angiotensin 1 to angiotensin 2. 6. Angiotensin 2 acts on smooth muscle to constrict blood vessels to increase blood pressure/volume. ★ Aldosterone (adrenal cortex) and angiotensin 2 stimulates kidneys to keep in sodium and water ★ Angiotensin2 also stimulates the pituitary to release the antidiuretic hormone, which will cause kidneys to retain water/increase blood volume/ ultimately increasing blood pressure - Atrial Natriuretic Hormone (ANH)- Secreted by atria when the cardiac cells are stretched due to an increase in blood volume. ➔ Sodium regulation Molecular Endocrine: Signals Transduction and Receptors ➔ Inhibition of renin secretion by juxtaglomerular apparatus ➔ Inhibits aldosterone release ➔ Natriuresis-Promotes diuresis and sodium excretion ● Hormone Action- Act on target cells, with specific receptor ➢ Two classes - Peptide- Peptide/Proteins/Glycoproteins/Modified Amino acids ➔ Receptor on cell surface: Lipophobic/Hydrophilic - Cannot cross cell membrane - Signals travels across cell membrane - Steroid- Complex of four rings but each has variable side chain ➔ Receptor inside cell: Lipophilic/Hydrophobic - Can cross cell membrane - Target receptor in cytosol or nucleus - Hormones That Bind to Intracellular Receptors Activate Genes ➔ Steroids-Estrogens/Progesterone/Testosterone ➔ Thyroid hormones- To nucleus ➔ Retinoids ● Cell Membrane Receptors- Lipophilic ➢ Tyrosine Kinase- Signal Transduction System - Lipophilic/Hydrophilic - Receptor- Tyrosine Kinase Monomers - It is a Receptor Kinase- Directly phosphorylates intracellular proteins to alter cellular activity ★ The peptide hormone insulin is a kinase ★ Growth hormone is not a kinase- But it activates intracellular kinases - Intrinsic Tyrosine Kinase Activity- Autophosphorylation of themselves and other substances - Phosphorylated proteins activate a sequence of events ➢ Hydrophilic Hormones use second messenger systems ➢ G-Protein Coupled Receptors - G Protein- Heterotrimeric, made of 3 subunits bound to protein (alpha/beta/gamma) ➔ Alpha- Has inactive GDP form that is swapped with active GTP ● GTP attached to alpha subunits- Dissociates from G protein ● Alpha subunits will migrate to adenylyl cyclase ● Types of Alpha Subunits - Gas- cAMP pathway activation Molecular Endocrine: Signals Transduction and Receptors - Gaq- cAMP pathway inhibition Gai- Associated with PIP2 and Ca2+ pathways ➢ PIP2- Phosphatidylinositol 4,5-bisphosphate ➔ Beta/Gamma subunits can activate other cellular cascades - Linked to second-messenger generating enzyme by membrane G proteins (GPCRs)- Effector proteins are usually enzymes - Ligand will dissociate from G protein- cAMP is being degraded and cellular cAMP levels low. Protein Kinase A activation is also low - G Protein Activates the enzyme and the second messenger molecules are increased ➔ Link between receptor that gets signal and effector that carries out response - Cellular response depends on the type of G protein activated ➔ Some activate while other inhibit second messenger ➔ A single hormone can have distinct actions in 2 different cells - Active when bound to GTP and inactive when bound to GDP - G Protein and Cyclic Nucleotide Signaling- Signal Transduction ➔ Lipophobic ➔ When G protein receptor is activated, it interacts with a G proteinCausing it to lose its alpha subunit which will migrate and bind to adenylyl cyclase ➔ EX- Glucagon/Angiotensin/Vasopressin/ Antiduretic Hormone or ADH receptors ➢ Protein Kinase A- Activated by cAMP, also known as PKA or cAMP dependent protein kinase - PKA usually inactive as tetrameric holoenzyme ➔ Composition- Two catalytic and two regulatory units ➔ Regulatory units block catalytic centers- Regulatory units dissociate ➢ Active Protein Kinase A- Catalyzes transfer of phosphates from ATP to serine or threonine residues of protein substrates - Phosphorylation of specific protein to promote regions of DNA, increasing expression of specific genes ● Second Messengers ➢ Adenylyl Cascade- Intermembrane amplifier protein, produces cAMP - Activated by interaction with G protein - Produces second messenger- A cyclic nucleotide cAMP ➔ cAMP broken down by phosphodiesterase ➔ cAMP activates Protein Kinase A ➢ Phospholipase C Molecular Endocrine: Signals Transduction and Receptors - ● ● ● ● ● PIP2 acted on by effector phospholipase C Produces IP3 and DAG, both are second messengers ➔ Inositol Triphosphate (IP3)- Water soluble, travels to smooth ER - Binds to a ligand gated Ca2+ channel and causes the release of calcium in cytoplasm. The calcium can bind to protein kinase c to activate it - Calcium acts as second messenger ★ Intracellular concentration usually low while extracellular concentration is high ★ IP3 binds to smooth ER receptors to signal calcium release ★ Ca2+ initiates cellular responses by binding to calmodulin ➔ DAG - Binds to protein kinase c, activating it - Protein Kinase A and C similar both phosphorylate - BUT protein kinase c needs help from calcium Second Messenger Responses- Different receptors can produce the same second messengers ➢ EX of Different signals, same effect- Glucagon and epinephrine can both stimulate liver cells to mobilize glucose - Use same signal transduction pathway Receptor Subtypes- Single signaling molecules can have different effects in different cells. Multiple forms of same receptor ➢ Epinephrine has 9 isoforms- Encoded by different genes with similar sequenced but different cytoplasmic domains ➢ Different forms activate different G proteins- Leading to different signal transduction pathways ➢ GPCRs and RTKs can both activate the MAP kinase cascade and phospholipase C Effects of Hormones ➢ Liver- Glucagon and Epinephrine, gluconeogenesis and glycogenolysis ➢ Fat Cell- Glucagon/Epinephrine, Lipolysis ➢ Renal Cell- Vasopressin (ADH) and Parathyroid hormone, have various effects Cellular activities- Glucose metabolism/Modulation of membrane structure/Transcription regulation/Mediation of immune responses/ Regulation of cell growth and memory/ Cell proliferation Intracellular Receptors ➢ Ligand Binding Domain- Hormone binding ➢ DNA Binding Domain- Can be covered by heat shock protein Molecular Endocrine: Signals Transduction and Receptors ➢ The receptor hormone complex will translocate to the nucleus where the exposed DNA binding domain can bind to DNA ● Hormones That Use cAMP Dependent Pathways ➢ Anti-Diuretic Hormones (ADH)- Secreted by the hypothalamus, promotes water retention by the kidneys. ➢ Growth Hormones Releasing Hormone (GHRH)- Secreted by hypothalamus, stimulates synthesis and release of growth hormone ➢ Corticotropin Releasing Hormone (CRH)- Secreted by hypothalamus, stimulates synthesis and release of adrenocorticotropic hormone (ACTH) ➢ Adrenocorticotropic Hormone (ACTH) – Secreted by anterior pituitary gland. It stimulates the synthesis and release of Cortisol Thyroid Stimulating Hormone (TSH) – Secreted anterior pituitary gland, stimulates the synthesis and release of a thyroid hormone ➢ Luteinizing Hormone (LH) –Released by the anterior Pituitary, stimulates follicle maturation and ovulation. In men, it stimulates testosterone synthesis and spermatogenesis ➢ Follicle Stimulating Hormone (FSH) – Released by the anterior pituitary. It stimulates follicular development in women and spermatogenesis in males ➢ Parathyroid hormone (PTH) – Secreted by the Parathyroid gland. It increases blood calcium levels. ➢ Calcitonin –Secreted by the Parafollicular Cells of the Thyroid. It lowers blood calcium levels. ➢ Glucagon –Secreted by the alpha cells of the Pancreas. It stimulates glycogenosis. ➢ Epinephrine –Released by the adrenal medulla. It stimulates a variety of tissue and organ responses including glycogenosis, increases in heart rate, relaxation of bronchial smooth muscle ➢ Gαi inhibits the production of cAMP from ATP. Insulin works through Gαi (inhibitory) second messenger proteins. ● Hormones using PIP2/Ca2+ Dependent Pathways ➢ Antidiuretic Hormone (ADH)- Secreted by posterior pituitary, causes vasoconstriction/platelet aggregation/uterine contraction/ glucocorticoid release ➢ Thyrotropin Releasing Hormone (TRH)- Secreted by hypothalamus, stimulates TSH synthesis and release. ➢ Thyroid Stimulating Hormone (TSH)- Secreted from anterior pituitary, stimulates thyroid hormone synthesis and release. ➢ Angiotensin 2- Final processing occurs in the lungs, stimulates aldosterone synthesis and release. Molecular Endocrine: Signals Transduction and Receptors ● ● ● ● ● ➢ Gonadotropin Releasing Hormone (GnRH)- Secreted by hypothalamus, stimulates the synthesis and release of FSH and LH Hypothalamus- Part of the brain, acts as integration and control center ➢ Composed of neurons and projecting to various parts of the brain ➢ Role- Regulation of physiological systems ➢ Purpose- Maintenance of homeostasis ➢ Connected to pituitary gland/hypophysis ➢ Mediates input from various parts of the body including the CNS ➢ Activating specific efferent or response pathway - Activation- Change in internal environment - Outcome- Restoring homeostasis Pituitary gland/Hypophysis- Hangs from hypothalamus ➢ Anterior pituitary hormones- TSH/ACTH/LH/FSH/GH/Prolactin ➢ Posterior pituitary- Posterior pituitary is neural tissue and consists of distal axons of the hypothalamus magnocellular neurons-neuroendocrine cells - Oxytocin- Like ADH, made of 9 amino acids ➔ Regulates reproductive behavior- Stimulates milk ejection reflex and uterine contractions during labor - Vasopressin/ADH- Peptide hormone that stimulates water reabsorption by the kidney, inhibiting diuresis (urine production) Vasopressin System ➢ V1 (Gaq)- Vasoconstriction/Platelet aggregation/Uterine contraction ➢ V2 (Gas)- Increases water reabsorption by changing the water permeability of the renal collecting ducts Anterior Pituitary Disorders ➢ Growth hormone- Stimulates protein synthesis and growth of muscles and CT - Stimulates production of insulin-like growth factors that stimulate cell division in epiphyseal growth plates-elongation of bone (Pituitary dwarfism) - Acromegaly and Gigantism -Insulin also regulates protein, lipid, and carbohydrate metabolism- Tumor can cause hypopituitarism- Decrease in hormonal output - Hyperplasia of pituitary gland results in abnormally high level of growth hormone- Growth hormone secreting pituitary tumor - Clinical Signs-Pituitary enlargement/Gigantism in childhood or acromegaly/ Arthritis /Carpal tunnel syndrome/ Skin tags/ Oily skin/ Sleep apnea/ CHF - Treatment- Surgery/Radiation/Suppression of GH/GH receptor antagonist Diabetes Insipidus- Disorder where large volume of hypotonic/dilute urine is produced ➢ Caused by absence of vasopressin or inadequate response to vasopressin Molecular Endocrine: Signals Transduction and Receptors ➢ Diabetes Mellitus- Hypertonic/concentrated sweet urine ➢ Pathophysiology of excess water intake - Decreased synthesis/secretion of vasopressin - Accelerated metabolism of vasopressin - Lack of appropriate response to vasopressin by kidneys ➢ Diabetes insipidus patients have intact thirst mechanism (no dehydration) but present with polyuria and polydipsia-thirst ➢ Patients with decreased thirst become dehydrated and develop severe hypernatremia with negative effects on the CNS ● Thyroid Gland ➢ Many follicles that … ➢ Secretes thyroid hormones- Thyroxine (T4-four iodine molecules) and Triiodothyronine (T3-three iodine molecules) ➢ Thyroid requires iodine to produce T3 and T4- Increase metabolism, stimulate the body cells to metabolize glucose and utilize more energy ➢ Other Hormone- Calcitonin - Peptide hormone - Stimulates uptake of calcium into bones to lower calcium levels in the blood ➢ Goiter- Enlarged thyroid from iodine deficiency ➢ Thyroid hormones bind to receptors in the nucleus ➢ Thyroid hormones regulates enzymes controlling carbohydrate and lipid metabolism - Hyperthyroidism vs hyperthyroidism in adults ● Parathyroid Gland- 4 Small glands attached to thyroid gland ➢ Production of parathyroid hormone-PTH, raises calcium blood levels ➢ Stimulates osteoclasts to dissolve calcium phosphate crystals in the bone matrix and release calcium into the blood ➢ Stimulates the kidneys to reabsorb calcium from the urine ➢ Vitamin D is activated by a PTH controlled enzyme- Stimulates the intestinal absorption of calcium ● Adrenal Glands ➢ Medulla- Inner - Stimulated by sympathetic nervous system- Fight + Fight - Secretes catecholamines epinephrine and norepinephrine - Catecholamines ★ Short term stress response ★ Cardiovascular/ Carbohydrate and Lipid metabolism/ CNS ➢ Cortex-Outer - Stimulated by anterior pituitary hormone ACTH Molecular Endocrine: Signals Transduction and Receptors - Corticosteroids ★ Glucocorticoids- Cortisol; maintain glucose homeostasis - Long term stress response - Lipid and carbohydrate metabolism/ immune system/ damage repair ★ Mineralocorticoid- Aldosterone; mineral balance ➢ Cushings- Chronically high glucocorticoids ★ Lipolysis and fat redistribution- Buffalo hump/ Moon face ★ Occurs- Long Term high dose of glucocorticoid medicinesPrednisone/Prednisolone/Dexamethasone ★ Can also happen because of: Pituitary tumor that secretes ACTH or benign tumor of adrenal that secretes excess cortisol (does not need ACTH stimulation) ● Pancreas- Exocrine and Endocrine ➢ Exocrine function- Connected to duodenum by pancreatic duct ➢ Endocrine function- Islets of langerhan, govern blood glucose through antagonistic glucagon and insulin ➢ Insulin- Beta cells - Uptake of glucose into cell - Storage as glycogen in the liver/muscles/fat ➢ Glucagon- Alpha cells - Promotes hydrolysis of glycogen in liver/fat ➢ Diabetics- Cannot take up glucose from blood ★ Type 1- Insulin dependent - Lack of beta cells - Daily injections of insulin as treatment ★ Type 2- Non-insulin dependent - Majority - Low number of insulin receptor - Diet and exercise ● Miscellaneous Hormones ➢ Atrial natriuretic hormone- Right atrium of heart; promotes salt and water excretion ➢ Erythropoietin- Secreted by kidney; stimulates bone marrow to synthesize RBCS ● Sexual Differentiation ➢ Male and females identical: 1 to 6th week of development ➢ 7th week: Primary reproductive organs start to develop; hormones produced by organs determine if embryo is male or female ➢ Testes or ovaries Molecular Endocrine: Signals Transduction and Receptors ➢ ➢ ➢ ➢ - Y and X chromosomes determine sex - Y- Testis - Absence of Y- Ovaries Y chromosome - SRY gene directs testicular determine factor (TDF) synthesis - TDF binds to DNA, causing differentiation of cells from genital ridges into testes - SRY alone can induce male differentiation (XX mice/some humans) - SRY and TDF don't require androgen or functional androgen receptors Male Hormonal Regulation - Hypothalamus controls testes sexual function - Gonadotropin releasing hormone (GnRH) causes anterior pituitary to release Follicle stimulating hormone (FSH) and Luteinizing hormone (LH) ★ FSH- Stimulates sperm production is seminiferous tubules ★ LH- Testosterone production in interstitial cells of testes ★ Negative feedback regulation ★ Inhibin downregulates FSH synthesis and inhibits FSH secretion - Secreted by sertoli cells- Located in seminiferous tubules inside testes - Androgens stimulates inhibin production Seminiferous Tubules - Interstitial cells secrete androgens, lie between seminiferous tubules - Most important androgen- Testosterone - Testerone maintains male secondary sex characteristics: Taller/ hair distribution/more muscle AIS- Sufferers have male chromosomes and male glands with feminization of external genitals (testicular feminization) - X linked recessive disease with mutation in androgen receptor (AR) causes.. ➔ Functioning Y and abnormal X ➔ AR is located on longarm of X chromosome ➔ AR gene has instruction for protein called androgen receptor, allows cells to respond to androgens (testerone) and direct male sex development ➔ Androgens regulate- Hair growth and sex drive ➔ Mutations- Complete/partial deletion, point mutations, and small insertions or deletion ➔ Pts still have testes - Testis determining factor (TDF) - Sex determining region of Y chromosome Molecular Endocrine: Signals Transduction and Receptors - ➢ ➢ ➢ ➢ ➢ Types ★ CAIS- Complete - External female genitals but lacking internal female organs ★ PAIS-Partial - External genitals appear on spectrum- Male to female ★ MAIS-Mild/Rare - Impaired sperm development or masculinization AIS SPECTRUM- Depends on degree of mutation in AR gene ★ 1- PAIS - Male genitals and infertile ★ 2-PAIS - Male genitals with mild under masculinization ★ 3-PAIS - Male genitals with severe under masculinization ★ 4-PAIS - Ambiguous genitals ★ 5-PAIS - Essential female genitals but with enlarged clitoris ★ 6-PAIS - Female genitals with pubic/underarm hair ★ 7-CAIS - Female genitals with little to no pubic/underarm hair Testicles secrete- Testosterone and Mullerian Duct Inhibitor - Testosterone converted to dihydrotesterone - Mullerian duct inhibitor is a suppressor- Produced by sertoli cells, it causes mullerian ducts to degenerate preventing the development of internal female sex organs in males Wolffian ducts- Develop remainder of internal male reproductive system and suppress mullerian ducts - Defective AR causes wolffian ducts and genitals to not respond to androgens (testerone/dihydrotesterone) Female carriers- Maternal relatives affected by AIS ★ XX female: Delayed puberty/ Decreased hair in pubic and axillary regions/ Decreased bone density AIS Therapy ★ Gonadectomy- Teste removal ★ Vaginal lengthening ★ Genital plastic surgery - Reconstruction of female genitals if masculinization occurs - Phalloplasty/Vaginoplasty/Clitorectomy Molecular Endocrine: Signals Transduction and Receptors ➢ AIS Treatments- Hormone replacement therapy ● Female- Estrogen - Progesterone- Reduces risk of breasts ● Male-Testerone and DHT ● Orally/Transdermal/Implant/Injection ● Prevents osteoporosis- 10/11 years - Body responds as if patient were postmenopausal- Bone density decreases and osteoporosis occurs ➢ Androgen-Insensitivity Syndrome - Genetically male XY - Testosterone is secreted by target cells lack receptors - NO masculinization