Hormones Prof. Dr. Volker Haucke Institut für Chemie-Biochemie Takustrasse 6 Tel. 030-8385-6920 (Sekret.) 030-8385-6922 (direkt) e-mail: vhaucke@chemie.fu-berlin.de http://userpage.chemie.fu-berlin.de/biochemie/aghaucke/teaching.html
Hormones (Lehninger, Principles of Biochemistry, chapter 23, pp. 884-900) 1. Classes of Hormones & Principles of Hormone Action 2. Major Endocrine Systems 3. The Leptin System
Hormones (Lehninger, Principles of Biochemistry, chapter 23, pp. 884-900) 1. Classes of Hormones & Principles of Hormone Action 2. Major Endocrine Systems 3. The Leptin System
Hormone action in animal cells Signals Physiological Processes Regulated by Hormones maintenance of blood pressure blood volume electrolyte balance embryogenesis sexual differentiation development & reproduction a. autocrine (acting on itself) b. paracrine (acting on near neighbour) c. endocrine (carried via blood to distant target cell) hunger, eating behavior digestion
Characteristics of hormone-induced signal transduction events example: walking from bright sunlight into a dark room
Hormone binding to its receptor may occur at the membrane or intracellular 1. hormone-gated ion channel: change in membrane potential 4. transcriptional regulation by nuclear hormone-receptor complex 2. hormone-induced activation of receptor enzyme 3. hormone-induced second messenger generation
Distinct chemical classes of molecules may act as hormones
Distinct chemical classes of molecules may act as hormones Examples: insulin; glucagon; somatostatin; hormones secreted by hypothalamus (releasing factors) and pituitary (LH; FSH; Vasopressin etc.)
Insulin is secreted from pancreatic β-cells following activation ER: co-translational translocation into lumen; cleavage of signal peptide; disulfide bond formation secretory granules: conversion into active insulin by endoproteases & carboxypeptididase (induced by high blood glucose)
Insulin is secreted from pancreatic β-cells following activation ER: co-translational translocation into lumen; cleavage of signal peptide; disulfide bond formation secretory granules: conversion into active insulin by endoproteases & carboxypeptididase (induced by high blood glucose)
Proopiomelanocortin (POMC) undergoes cleavage into many active peptide hormones (hypothalamus)
Distinct chemical classes of molecules may act as hormones Examples: dopamine; norepinephrine; epinephrine
Catecholamines are derived from tyrosine
Catecholamines are derived from tyrosine
Steroid and retinoid hormones as well as vitamin D act through nuclear hormone receptors
Steroid and retinoid hormones as well as vitamin D act through nuclear hormone receptors Steroid hormones metabolism of carbohydrates electrolytes (blood) sexual development & behavior
Steroid and retinoid hormones as well as vitamin D act through nuclear hormone receptors Steroid hormones Vitamin D metabolism of carbohydrates electrolytes (blood) sexual development & behavior calcium uptake & mobilization (bone) Retinoic Acid (RA) cell differentiation (i.e. skin, cornea, immune system etc.)
Steroid and retinoid hormones as well as vitamin D act through nuclear hormone receptors
Steroid receptors are Zn-finger containing transcription factors that recognize specific DNA sequences termed hormone response elements (HRE)
Hormones (Lehninger, Principles of Biochemistry, chapter 23, pp. 884-900) 1. Classes of Hormones & Principles of Hormone Action 2. Major Endocrine Systems 3. The Leptin System
Endocrine tissues are regulated via the hypothalamus-pituitary systems Characteristics: Amplification Regulation
Hormone release cascades are regulated by feedback inhibition by the ultimate hormone -release triggered by hypothalamic nerve endings -release triggered by hypothalamic hormones from the blood
Hormones (Lehninger, Principles of Biochemistry, chapter 23, pp. 884-900) 1. Classes of Hormones & Principles of Hormone Action 2. Major Endocrine Systems 3. The Leptin System
Hypothalamus regulation of food intake involves leptin, a protein produced in adipocytes, and a cognate leptin receptor in hypothalamic neurons Leptin receptor: -encoded by DB (diabetic) locus -transmembrane protein at the PM signaling via JAK-STAT pathway -expressed in: hypothalamus (high), pancreatic β-cells, adrenal cortex (low) Leptin effects: (1) signals sufficient fat reserves: reduction in fuel intake (appetite) (2) stimulation of sympathetic neurons (i.e. norepinephrine secretion) to increase blood pressure, heart rate & thermogenesis (uncoupling electron transport from ATP synthesis via uncoupling protein [UCP-1]) (3) mechanisms: Neuropeptide synthesis (i.e. NPY)
Defects in leptin production (or recognition) lead to adipositas
Hypothalamus regulation of food intake involves leptin, a protein produced in adipocytes, and a cognate leptin receptor in hypothalamic neurons (appetite-suppressing) (appetite-stimulating; theromogenesis reducing) leptin -/-: increase in NPY
Leptin signaling occurs via the JAK-STAT pathway 1. leptin binding & receptor dimerization 2. phosphorylation of ligand occupied receptor by Janus kinase (JAK) on specific Tyr residues 3. docking of STAT proteins (signal transducers and activators of transcription) via SH2 domains to phospho-tyr 4. phosphorylation of STATs by JAK, STAT dimerization 4. nuclear import & transcriptional regulation
SUMMARY 1. Hormones are chemicallydiverse messengers that may exhibit autocrine (rare), paracrine, or endocrine actions. 2. Signaling may occur via plasma membrane-localized receptor enzymes, downstream signaling cascades, or nuclear hormone-receptor complexes. 3. Peptide hormones such as insulin or proopiomelanocortin (POMC)-derived peptides are proteolytically processed from inactive prohormones upon passage into secretory vesicles. These signal via membrane-bound receptors such as tyrosine kinases or G- protein coupled receptors. 4. Catecholamine hormones are derived from tyrosine. Steroid hormones (derived from cholesterol), retinoid hormones (derived from vitamin A), and vitamin D hormones act through nuclear hormone-receptor complexes that act as transcription factors. 5. Nerve impulses stimulate the hypothalamus to send hormones to the pituitary gland to regulate release of tropic hormones. The anterior pituitary hormones in turn stimulate other endocrine glands including the tyhroid, adrenals, and the pancreas to secrete hormones. This hypothalamic-pituitary system is subject to feedback inhibition. 6. Leptin, a small protein, produced in response to abundant fat reserves by adipocytes acts via a membrane receptor in the hypothalamus that triggers the JAK-STAT signaling pathway resulting in secretion of neuropeptides and actication of sympathetic neurons to elicit activity. Leptin thus regulates body weight and feeding behavior.