Human Physiology Unit-1 Intercellular Communication BY DR BOOMINATHAN

Human Physiology: Unit-1 Intercellular Communication BY DR BOOMINATHAN Ph. D. M. Sc. , (Med. Bio, JIPMER), M. Sc. , (FGSWI, Israel), Ph. D (NUS, SINGAPORE) PONDICHERRY UNIVERSITY V Lecture 14/August/2012 Source: Collected from different sources on the internet and modified by Dr Boominathan Ph. D.

Intercellular Commication

Intercellular Communication • Cells of body must communicate with one another • Coordinates organ systems • Takes place directly: – Physical contact between cells • Gap junctions • Direct linkage of surface markers • Or indirectly – Extracellular chemical messengers or signal molecules – Specific to target cell receptors

Chemical Messengers • Four types of chemical messengers – Paracrines • Local chemical messengers • Exert effect only on neighboring cells in immediate environment of secretion site – Neurotransmitters • Short-range chemical messengers • Diffuse across narrow space to act locally on adjoining target cell (another neuron, a muscle, or a gland)

General Schemes of Intercellular Signalling Extracellular signaling molecules released by cells occurs over distances from a few microns – autocrine (c) and paracrine (b) signaling to several meters in endocrine (a) signaling. In some instances, receptor proteins attached to the membrane of one cell interact directly with receptors on an adjacent cell (d). © 2000 by W. H. Freeman and Company. All rights reserved.

Paracrine secretion

Neurotransmitter secretion

Chemical Messengers – Hormones • Long-range messengers • Secreted into blood by endocrine glands in response to appropriate signal • Exert effect on target cells some distance away from release site – Neurohormones • Hormones released into blood by neurosecretory neurons • Distributed through blood to distant target cells

Chemical Messengers • Cell responses brought about primarily by signal transduction – Incoming signals conveyed to target cell’s interior • Binding of extracellular messenger (first messenger) to receptor brings about intracellular response by either – Opening or closing channels • Chemically gated receptor channel – Activating second-messenger systems • Activated by first messenger – Receptor-enzyme • Relays message to intracellular proteins that carry out dictated response – G-protein coupled receptor

Receptor-enzyme: Tyrosine kinase pathway

Hormones • Endocrinology – Study of homeostatic activities accomplished by hormones • Two distinct groups of hormones based on their solubility properties – Hydrophilic hormones • Highly water soluble • Low lipid solubility – Lipophilic hormones • High lipid solubility • Poorly soluble in water

Mechanism of hydrophilic hormones via cyclic AMP second messenger pathway

Mechanism of action of hormones Lipophilic hormones Hydrophilic hormones

Comparison of Nervous System and Endocrine System

Animation: Mechanism of action of a peptide hormone

Animation: Mechanism of action of a steroid hormone

Questions 1. 2. 3. 4. 5. 6. 7. 8. 9. There are 3 ways cells communicate. The 2 direct means of communication is through ______ and ________. Cells indirectly communicate through ________. Name and describe the 4 types of chemical messengers. Include which fluid medium they travel through: blood, extracellular fluid, intracellular fluid. Why is a neurotransmitter different than paracrine signalling? What is a ligand? What is a receptor? How does a chemical messenger “know” which organ to affect? Name 3 ways that an extracellular chemical messenger can bring about an intracellular response. Is the response between a chemical messenger and a particular receptor always the same? How can a chemical receptor elicit a different response inside a cell? In a second messenger system, where does the first messenger bind? Where is the second messenger?

Questions 11. There are 2 major 2 nd messengers: cyclic AMP and Ca 2+. Describe the action of a hydrophilic hormone via activation of the cyclic AMP 2 nd messenger pathway. If you draw pictures, you must label everything and explain what is happening. 12. How does using an 2 nd messenger system amplify the response inside the cell? 13. How do some chemical messengers affect gene activity (hence, protein synthesis) within a cell? 14. Which type of hormone can affect gene activity, hydrophilic or lipophilic? Why?

INTRACELLULAR SIGNAL TRANSDUCTION: A Journey from the Plasma Membrane to the Nucleus (with interesting stops along the way) Thanks to Paula Tracy, Ph. D. paula. tracy@uvm. edu

INTRACELLULAR SIGNALING: Signal Transduction Cell membranes, as well as the cell cytoplasm and even the cell nucleus, contain cell-specific receptors for various ligands, which are involved in outside-inside signaling, i. e. signal transduction. Ligands include hormones, growth factors, cytokines, prostaglandins and proteases. Hormones are involved in a variety of metabolic processes that maintain homeostasis e. g. fuel metabolism. Particularly noteworthy in that regard are glucagon, insulin , epinephrine and norepinephrine. Growth factors are involved in mitogenesis, whereas cytokines play critical roles in the differentiation, proliferation and function of various cell lineages. . Interaction of such ligands with their membrane, cell-specific receptors or intracellular receptors causes conformational changes in the receptor and, in many instances receptorassociated cytoplasmic proteins. Such events result in the initiation of a cascade of importance, but as yet incompletely understood, events leading to e. g. enzyme activation, differentiation and/or cell division.

General Schemes of Intercellular Signalling Extracellular signaling molecules released by cells occurs over distances from a few microns – autocrine (c) and paracrine (b) signaling to several meters in endocrine (a) signaling. In some instances, receptor proteins attached to the membrane of one cell interact directly with receptors on an adjacent cell (d). © 2000 by W. H. Freeman and Company. All rights reserved.

FORCES DRIVING SELECTION OF CURRENT MECHANISMS Need for coordinated intercellular communication Need to translate extracellular signals into series of intracellular events, while allowing for specificity Specificity Determinants: 1. Specific receptors on or in the target cells recognize an appropriate ligand. 2. Specific response to receptor occupancy - effector pathways Diversity of intercellular communication is achieved with hundreds of signaling molecules, including. . . Proteins, small peptides, amino acids, nucleotides, steroids, fatty acid derivatives, and even dissolved gases such as NO and CO

Intracellular receptors: Receptor Classes - signaling molecules include steroid hormones, retinoids, thyroxine, etc - receptor-hormone complex acts a transcription factor to alter transcription of certain genes Cell surface receptors: - signaling molecules include peptide hormones, ephineprines, insulin, growth factors, cytokines, etc -binding, and subsequent events, triggers an or in the cytosolic concentration of a second messenger; or the activated, bound receptor acts as a scaffold to recruit and activate other intracellular proteins © 2000 by W. H. Freeman and Company. All rights reserved.

ADVANTAGES 1. Each cell is programmed to respond to specific combinations of signaling molecules 2. Different cells can respond differently to the same chemical signal. Molecular Biology of the Cell, 2002

HORMONES - First class of signaling molecules defined Secreted from endocrine cells - specialized signaling cells that control the behavior of an organism as a whole: 1. Differ from other intracellular mediators 2. Usually stimulate metabolic activities in tissues remote from the secretory organ 3. Active at very low concentrations (p. M - M) 4. Response to hormonal signal comes as a direct and rapid result of its secretion 5. Metabolized rapidly so effects are, in most instances, short-lived, leading to rapid adaptations to metabolic changes Hormone types: 1. Peptides or polypeptides - insulin, glucagon, growth hormone, insulin-like growth factors, vasopressin, prolactin…. 2. Glycoproteins - follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH)… 3. Steroids - glucocorticoids (aldosterone, cortisol), steroids (progesterone, testosterone), retinoic acid… 4. Amino acid derivatives - epinephrine, norepinephrine, thyroxine, triidothyronine

AGONISTS vs. ANTAGONISTS Agonist mimics a hormone in binding productively to a receptor Antagonist mimics a hormone stereochemically, but binds to the receptor non-productively, inhibiting the action of the natural hormone Agonist e. g. important therapy in asthma Hormone binds 2 receptor in lung bronchial relaxation binds 2 receptor in heart muscle increased heart rate Antagonist control heart beat

RECEPTOR CHARACTERISTICS 1. Participates in transduction of the signal from the external messenger to some component of the metabolic machinery 2. Has at least one additional functional site which is altered by ligand binding (allosteric site) 3. Ligand binding to receptors is saturable, resembling Michaelis-Menten kinetics © 2000 by W. H. Freeman and Company. All rights reserved. 4. Ligand-receptor interaction characterized by tight binding (Kd = p. M - M)

Molecular Biology of the Cell, 2002 Simple Intracellular Signaling Induced by an Extracellular Signaling Molecule A signaling molecule activates its receptor activation of an intracellular signaling pathway, i. e. a series of signaling proteins, which may interact with a target protein to change the behavior of the cell.

Glucagon Epinephrine Thrombin Insulin Growth factors Molecular Biology of the Cell, 2002 THREE LARGEST CLASSES OF CELL SURFACE RECEPTORS