MCB 3210/5210 Molecular Endocrinology (I)

1. MCB 3210/5210 Molecular Endocrinology (I) • Instructor: • Propfessors Thomas T. Chen, Office: TLS Rm 413A; Tel: 860-486-5481; E-mail: Thomas.Chen@uconn.edu • Professor Jianjun Sun, Office: PBB 117A; Tel: 860-486-5481; E-mail: Jianjun.Sun@uconn.edu • Office hour: Tue 1:00-3:00 p.m. or by appointment • Class Meeting Time: Tue and Thu 11:00 a.m. to 12:15 p.m. in TLS Rm 263 • Text Book: • Recommended textbook: Vertebrate Endocrinology 5th ed. by David O. Norris • Some original papers will be assigned in class for additional reading • Course Grade: • For MCB 3210: average of two exams (Mid-term and Final) • For MCB 5210: average of two exams (70%) + one in class presentation and a 20-page essay on the same topic of presentation (30%)

2. MCB 3210/5210 Molecular Endocrinology (II) • Two Lecture Exams: • Exam I: Tue, October 14th • Exam II: During the final exam week (to be announced) • Duration of lecture per period: 75 min • Exam questions will consist of short or long answers and problem solving questions. Materials will be taken from lecture materials and the assigned reading materials in the textbook and original research papers • Lecture materials will be posted on the website. Each student is responsible for printing out the materials from the website and bring to class for the lectures • Class website: http://www.sp.uconn.edu/~ttc02001/MCB3210-5210/ • An extra credit essay paper (20 pages, double-space)

3. I. Introduction

4. Molecular Endocrinology • Molecular Endocrinology: Studies of structures, synthesis and actions of hormones (bioregulators) at cellular and molecular levels • Definition of hormone: • Classic definition: Hormones are chemical substances produced by specialized tissues (endocrine glands) and secreted into the blood stream, where they are carried to target organs • Broader definition: Hormone are chemicals, non-nutrients, intracellular messengers that are effective at micromolar concentrations or less. In other words hormones are chemical substances that carry information between two or more cell types. They are also called as “bioregulators” • Discrepancies between the classic and the broader definitions: • Specialized tissue for hormone synthesis (vs. multiple tissues) • Blood for hormone distribution (vs. blood, intercellular fluid) • A separate organ for hormone action (vs. multiple target tissues)

5. Origins of Chemical Communication • Early cells living in the primordial seas developed “receptors” for recognition of water-soluble toxins, nutrients and internal “receptors” for lipids that could readily pass through the membrane. Some of these “receptors” transferred these molecules into the cell for metabolism or detoxification • Besides accumulating molecules intracellularly, early cells also released special molecules into the environment that were detected via receptors on other cells and served as a mechanism for cell-to-cell communication. Various features of these ancient mechanisms for accumulation, detoxification, metabolism, and chemical communication have persisted in one form or another in all living cells to this day

6. Categoreies of Bioregulators • Chemical communication involves: • Neurocrines, including neurotransmitters or neuromodulators • Neurohormones • Hormones • Autocrine/paracrine regulators • Ectohormones (semiochemicals) • The liver and kidney serve as major sites for the metabolism and excretion of bioregulators.

7. Chemical Bioregulation • Bioregulation is defined as secretion of: • The endocrine system • The nervous system • The immune system • Virtually all cells in the body that use chemicals to communicate with one another • Bioregulators

8. Types of Regulators

9. Some Mammalian Neurocrine Regulators The separation of neural and endocrine systems have become more blurred when it was learned that some established hormones also were produced within the nervous system where they function as neurotransmitters or neuro-modulators

10. Some Important Terms • Endocrine glands • Hormones • Receptors • Hormone-receptor complex • Bioregulation, bioregulators • Environmental endocrinology • Endocrine disruption, endocrine disrupting chemicals (EDCs), endocrine active chemicals (EACs) • Diethylstilbestrol (DES), DDT, polychlorinated biphenyls (PCBs) (examples of EDCs) are known endocrine disruptors

11. Some Terms • Cytocrine: local hormones including growth factors, mitogenic regulators, embryonic tissue-inducing substances, secretogogues (secretion-enhancing factors), inhibitors and immune regulators. These factors can act as autocrines or paracrines • Intracrines: Chemical messengers (secondary messengers or transcription factors) that govern intracellular events • Endocrines: Hormones • Ectohormones (semiochemicals): Chemical messengers secreted from one organism into the environment that affect the physiology or behavior of another organism. Example: pheromones (primer pheromone, releaser pheromone), Allelomes (allomones and kairmones)

12. Chemical Nature of Bioregulators • Peptide and protein hormones (most abundant): thyrotropin releasing hormone, GnRH, GH, PRL, insulin etc. • Amino acid derivatives: thyroid hormone, epinephrine • Steriod hormones: testostrone, estrogen, cotisone etc. • Lipids: prostaglandin, retinoic acid etc. • Nucleotides: cAMP, cytokinins, 1-methylalanine etc. • Oligosaccharides: a-1,4-oligogalacturonide • Gases: CO, ethylene etc

13. Structural Diversity of Hormones • A. Thyrotropin releasing hormone • B. Epinephrine • C. Cortisol • D. Prostaglandin • E. Plated activating factor • F. Zeatin (a cytokinin) • G. a-1,4-oligogalacturonide (an elicitor) • H. ethylene

14. Functional Conceptualization of the Endocrine System

15. Organization of Bioregulator Systems • Neuroendocrine system: Brain (hypothalomus) and pituitary gland (producing tropic hormons and other hormones) • Classical endocrine glands: thyroid gland, adrenal glands, gonads, and liver • Independent endocrine glands: parathyroid glands, thymus, endocrine pancreas, organs of the gastrointestinal tract, pineal gland and the kidney • Tropic hormones: Hormones secreted by hypothalamus that regulate the secretion of peptide or protein hormone from pituitary glands, thyroid glands, adrenal cortex, gonads and liver • Table 1-3 in the textbook and the following few slides list many of these hormones. Please read.

16. Major Mammalian Endocrine Secretions (I) • Hypothalamus: • producing hypothalamus releasing neurohormones such as TRH, GnRH, CRH, GHRH, GH-RIH, PRIH, PRH, MRIH, MRH • Producing other neurohormones such as AVP, OXY, Endophines/enkephalins • Anterior pituitary: • Producing glycoprotein tropic hormones such as TSH, LH (leuteinizing hyormone), and FSH • Producing nonglycoprotein tropic hormone such as GH, PRL, ATCH, and melanotropin (MSH) • Thyroid gland: • Producing thyroid hormones (T3 and T4) and calcitonin • Gonads: • Ovary: producing estrogens, progestrone and inhibin • Testis: producing testostrone and other androgens,a d inhibin

17. Major Mammalian Endocrine Secretions (II) • Adrenal glands: • Adrenal cortex: producing aldosterone and corticosterone/ cortisol • Adrenal mediulli: producing epinephrine/norepinephine • Parathyroid gland: • Producing PTH • Endocrine pancreas: • Producing insulin, glucogon, pancreatic polypeptide & GH-RIH • Liver: • IGF-I and IGF-II • Adipose tissue: • Producing leptin • Kidney: • Producing erythropoietin, renin, and 1,25-dihydrocholecalciferol

18. Major Mammalian Endocrine Secretions (III) • Gastrointestinal system: • Stomach: producing gastrin and ghrelin • Small intestine: producing secretin, cholecystokinin, gastrin-rteleasing peptide, gastric inhibitory peptide, motilin, somatostatin and vasoactive intestinal peptide • Pineal gland: • producing melatonin • Immune system • Thymus: producing thymosins • Macrophages/lymphocytes: producing interleukin 1 and lnterleukin 2

19. Morphological Features of Bioregulator Secreting Cells Steroid secreting cells Growth hormone secreting cells

20. Organization of Endocrine Cells (A) Cells secreting growth hormone (orange) and gonadotropins (blue) in a pituitary gland; (B) Islet of insulin secreting cells (arrow) embedded within the darker stained exocrine pancreas; (C) Follicles from a thyroid gland showing a thin epithelium and pink colloid filling the lumen of the follicle. (D) Isolated clusters of testosterone secreting interstitial cells (arrow) located between seminiferous tubules in a testis.

21. Homeostasis • Defined by Walter B. Cannon: Balanced physiological systems operating in the organism to maintain a dynamic equilibrium (a relatively constant steady state) maintained within certain tolerable limits • This concept was originally used to describe the maintenance of blood parameters such as osmotic pressure, volume, hydrostatic pressure and levels of various simple chemicals Ca++, Na+ and glucose • It can be expanded to include all manner of physiological bioregulation at the level of organism and at the levels of molecular and cellular levels

22. Hormonal Control Systems • Negative feedback control: Rising levels of a hormone shuts down the production of the hormone so that its level can be maintained. Example: cortisol inhibits hypothalamus to produce CRF to control adrenal cortex to produce cortisol • Positive feedback control: Rising hormone levels stimulates further production of the hormone. Example: production of oxytocin near parturition • Cycle-dependent feedback control: Nagative and positive controls function together. Example: estrogen negative feedback control hypothalamus to produce more estrogen in nonmidcycle, but at midcycle, estrogen positive regulate hypothalamus to produce more estrogen to induce a surge of luteinizing hormone leading to ovulation

23. Feedback Regulation of Hormone Secretion • Negative Feedback • Positive Feedback • Cycle-dependent Feedback

24. Life History of a Hormone Liver and kidney are major sites of hormone metabolism and excretion

25. Endocrine Disruption of Homeostasis • The homeostasis in an organism can be profoundly affected by endocrine imbalances • Some examples of endocrine disorders: acromegaly goiter, type I and type II diabetes, rickets, Turner’s syndrome, polycystic ovary syndrome etc. • In recent years, endocrinologists have focused on the presence of chemicals in the environment that can potentially disrupt endocrine functions. These chemicals are called as “Endocrine Disrupting Compounds (EDCs)”. • EDCs can function directly to disrupt the activities of endocrine glands or mimics the activities of hormones • Examples of EDCs: • Insecticides such as DDT or metabolites of DDT • Herbicides such as atrazine, glyophoste • Fungicides such as vinclozolin • Industril or mining byproducts such as heavy metals, dioxins and PCBs • Estrogenic or anti-androgenic compounds • For details, see Table 1-6 in the textbook