Hormones, Receptors and Rhythms PDF

Section 1 Hormones, Receptors and Rhythms Part 1 Learning Objectives At the end of this section, students will recognize understand, and describe… vHormone vSignaling and response vRhythms vGeneral principles of endocrinology Need for cellular communication bc multicellular Not separate entities, al...

Section 1 Hormones, Receptors and Rhythms Part 1 Learning Objectives At the end of this section, students will recognize understand, and describe… vHormone vSignaling and response vRhythms vGeneral principles of endocrinology Need for cellular communication bc multicellular Not separate entities, all these are interconnected Differentiation Proliferation Homeostasis Main Network (communication) Systems vNervous system: Direct connection between organs similar to road/train vEndocrine system: Sending chemical messages (hormones) into the circulation can access any part of the body similar to air travail analogy only for transport, not speed (neural activity way faster than endocrine system) What is a hormone? vGreek “I excite” or “I arouse” or “to set in motion” vClassical definition vChemical messenger released by one type of cells and carried in the bloodstream to act on distant target cells go out of the cell vGeneral definition chemical signals vChemical messenger (released) from one cell to act on another cell vHormones vGrowth factors vCytokines/Chemokines vNeurotransmitters Ernest Starling William Bayliss Pioneers of endocrinology: discovered the first hormone secretin vMitogens/Morphogens vMembrane bound/ECM ligands Hormones are sometimes growth factors as well What is Endocrinology? vBranch of physiology – the study of endocrine gland and hormones vGreek/Latin - Endo = internal; Krine = secretion vEndocrine = internal secretion vWord “endocrinology” fits with the classical definition of hormone Homeostasis is achieved by a complex communication network of chemical signalling vHuman adult is composed of about 50 trillion cells vThese cells are coordinated by less than 24000 protein encoding genes vThe coordination is achieved by networking vOur understanding of these regulatory networks is still incomplete Homeostasis is achieved by a complex communication network 3 layers of signaling networks: vWithin cells intracellular vBetween groups of cells (tissues) intercellular vBetween tissues or organs Networks buffer against change: Homeostasis POSITIVE INTERACTIONS NEGATIVE INTERACTIONS PRESERVED INTERACTIONS INTERACTIONS NOT PRESERVED REVERSED INTERACTION NEW INTERACTION Even dramatic changes such as knocking out a gene may not change the output Z redundancy of communication network Nature of endocrine communication vSignals are generated in special cells (hormone producing cells). vTarget cells recognize such signals and respond to them. vThe type of response to a signal differs between cell types (liver cell has a different response than a muscle cell). vCells are exposed to many signals at the same time. Their response is an integrated response to all signals. Classes of signals based on generation and delivery cell secretes some signal that secretes the cell (ex: estrogen) neighbouring cells in same vicinity/tissue to other cells Endocrine glands vCells that synthesize hormones may be clustered (endocrine glands) or interspersed as pancreas, single cells in organs liver, ovary vComposition thyroid glands – Parenchyma (Secretory cells) – Blood vessels – No ducts if they have ducts: exocrine vPermanent or transient – Thyroid, adrenal, pancreas – Ovarian follicle and corpus luteum; placenta Endocrine Cell Protein hormone elongated bc heavy duty to produce protein for protein synthesis steroid hormone Lipid hormone circular bc steroidogenesis occurs there to store precursor necessary cleaves off vesicles in granules to store protein hormones steroidogenesis takes place there General characteristics of hormones vVery low in concentration v(ng/ml) or (pg/ml) vVery specific receptor vOne hormone, one receptor (typically!) Chemical nature of hormones CHO: glycosylation role in hormone, but not a chemical nature of hormones 1) Lipids vSteroids vEicosanoids or 2) Proteins vShort polypeptides vLarge proteins vChemical modification through glycosylation or 3) Amino acid derivatives like epinephrine and norepinephrine Lipid Hormones: Cholesterol derivatives vCholesterol is the precursor (contain sterol ring) go directly to the cell vHighly hydrophobic can during signalling vFound in cell membrane vSource of cholesterol Diet De Novo synthesis vDerivatives – Vitamin D; Bile acid (Lipid digestion and signaling); Steroid hormones (Sex and Adrenal steroids) Steroid hormones vAdrenal Mineralocorticoids – Affect mineral homeostasis Glucocorticoids – Affect glucose metabolism and immune function vGonads (testis and ovaries) Estrogens Progestogens Androgens 1 precursor: cholesterol sequential conversion of cholesterol in hormone (cascade) Steroidogenesis Some enzymes are in mitochondria and ER Steroidogenic enzymes depend on electron transfer proteins transfer electrons: redox —> hydrogenation, deoxygenation Mitochondrial electron transporters: ADR = Adrenodoxin reductase and Adx = adrenodoxin * * * * Microsomal electron transporters: POR = P450 oxidoreductase or B5 = cytochrome b5 * * * * Steroids of importance * Steroidogenesis Androgen Estrogen Aromatase CYP19A1 (C18H24O2) (C19H28O2) Chemically very similar but three-dimensional structure of the two molecules differs markedly sable conversion: hardly any difference between these 2 Subtle change in structure = big difference in signalling Synthesis of steroid hormones lipid soluble vDerived from cholesterol: Main source is circulatory LDL vHDL can be taken up and can also be synthesized from acetyl-CoA vCell specific expression of enzymes determines steroid production depending on the enzymes the machinery has, produces different hormones vSome enzymes are in the mitochondria (CYP11A1, CYP11B1, CYP11B2); some in the endoplasmic reticulum (CYP17A1, CYP21A2); some in both (HSD3B1/2, HSD17B, HSD11B1/2) vSteroid intermediates shuttle back and forth vMost steroids differ by minor modifications of side groups, often hydroxyl groups Lipid Hormones: Eicosanoids v Metabolites of 20-C fatty acid: Arachidonic acid v Prostaglandins Isolated from prostate Inflammatory reaction Reproduction Membrane Phospholipid Phospholipase A v Thromboxanes, leukotrienes, and prostacyclins HETE = Hydroxy-eicosatetraenoic acid Peptide (Protein) hormones vLarge polypeptides vLinear chain vSubunits vLinked by disulfide bridge(s) v3D structure vCritical for interaction with receptor vWater soluble Peptide hormones Human insulin Growth hormone Protein hormone synthesis Gene expression vTranscription vTranslation vPost-translational modification vCleaving of long amino acid chain (preprohormones) to generate small peptide hormones (e.g., GnRH, oxytocin, TRH) vInteraction and linking of subunits v3D structure Transcription of peptide hormones Hormone gene Translation of peptide hormones Start codon: AUG, Met Post-transcriptional modification CGRP = calcitonin gene related protein Post-translational modification joined together usually with disulphide bonds TSH e.g., Growth Hormone POMC – ACTH and MSH, Pro-glucagon – Glucagon and GLP1/2 Insulin Relaxin Thyroid Stimulating Hormone Luteinizing Hormone Glycosylation: effect on how signal is transduced or half-life Post-translational peptide modifications vLipophilic leader sequence (signal peptide) is cleaved by peptidase. create pro-hormone vFormation of disulfide bridges between cysteines and glycosylation. vTransport by vesicles into the Golgi. Further glycosylation and proteolytic cleavage. can be stored and after days or months, will be proceeded vPackaging into vesicles. Sometimes together with the signal arrives, vesicles in periphery of an activating peptidase. when cytoplasm packaging = storage Amino acid derived hormones vTyrosine derivatives – Thyroid hormones Thyroxine (T4) Triiodothyronine (T3) – Adrenal medulla Epinephrine Norepinephrine Dopamine Often used as neurotransmitters Storage of hormones vHydrophilic hormones are stored vStored in secretory vesicles (granules) in the cytoplasm vMovement to the cell membrane mediated is by microtubules (cytoskeleton) and microfilament vCells require a stimulus to activate and release the stored prohormone 35 Hydrophobic vs Hydrophilic hormones bc blood is aqueous bc can’t cross cell membrane Lipid Synthesis when necessary Protein 39 Control of synthesis and secretion v Neural inputs – Brain – Hypothalamus v Hormonal stimulation/inhibition – Releasing factors/hormones – Inhibitory factors – Feedback system v Metabolic status – Stress – Blood concentrations of substances Ca Glucose Water 40