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Cell-to-cell communication Transduction pathways L. 3. 13.09.10 Cellular Communication Everything in animal does involve communication among cells Example: moving, digesting food Cell signaling – communication between cells Signaling cell sends a signal (usually a chemical) Target cell receives the signal and responds to it Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Types of Cell Signaling Direct Signaling cell and target cell connected by gap junctions Signal passed directly from one cell to another Indirect Signaling cell releases chemical messenger Chemical messenger carried in extracellular fluid Some may be secreted into environment Chemical messenger binds to a receptor on target cell Activation of signal transduction pathway Response in target cell Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Indirect Signaling Over Short Distance Short distance Paracrine Chemical messenger diffuses to nearby cell Autocrine Chemical message diffuses back to signaling cell Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Indirect Signaling Over Long Distance Long distances Endocrine System Chemical messenger (hormone) transported by circulatory system Nervous System Electrical signal travels along a neuron and chemical messenger (neurotransmitter) is released Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings CHEMICAL REGULATORY AGENTS Communication & Coordination (C02, 02, H+) (Ca2+) cAMP cGMP ACh, GABA not secreted by specific glands non-specific metabolic by-products intracellular messenger ECF or SR coupling agent intracellular messenger second messenger for many hormones neurotransmitters neuromodulators insulin estrogen, testosterone antidiuretic hormone bombykol HORMONES pheromone Types of Cell Signaling Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.1 Direct Signaling Gap junctions Specialized protein complexes create an aqueous pore between adjacent cells Movement of ions between cells Changes in membrane potential Chemical messengers can travel through the gap junction Example: cAMP Opening and closing of gap junction can be regulated Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings GAP JUNCTIONS cells coupled metabolically and electrically via hydrophilic channels Passage of: - inorganic ions - small water-soluble molecules: amino acids sugars nucleotides - electrical signals -labile: Fig. 3.2 The structure of gap junctions close in response to high [Ca2+]ICF or high [H+]ICF Indirect Signaling Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Table 3.1 CELLULAR COMMUNICATION: AUTOCRINE and PARACRINE CELL SIGNALING Secreted chemical affects secreting cell (autocrine) nearby cell (paracrine) Chemical Messengers Six classes of chemical messengers Peptides Steroids Amines Lipids Purines Gases Structure of chemical messenger (especially hydrophilic vs. hydrophobic) affects signaling mechanism Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Indirect Signaling Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Table 3.2 MECHANISM OF ACTION OF hydrophilic chemical messengers (e.g. LIPID-INSOLUBLE HORMONES) peptides and proteins, catecholamines •usually not bound to carrier protein •do not readily diffuse across membrane •bind to membrane receptor •H-R complex triggers production of 2nd messenger cAMP, cGMP (cyclic nucleotide monophosphates) IP3 (inositol phospholipids) Ca2+ ions •rapid, short-lived responses; usually metabolic Transport of chemical messenger to the target cell MECHANISM OF ACTION OF hydrophobic chemical messengers (e. g. LIPID-SOLUBLE HORMONES steroid hormones thyroid hormones •bound to carrier protein in blood •readily diffuse across membrane •bind to cytoplasmic or nuclear receptor •H-R complex binds to regulatory portions of DNA •stimulate (or inhibit) transcription of specific genes •and specific proteins •effects persist for hours to days Transport of chemical messenger to the target cell HORMONES •BIOLOGICALLY ACTIVE CHEMICALS •SYNTHESIZED, STORED, AND SECRETED BY: ENDOCRINE GLANDS (ductless) e.g. pancreas, thyroid, gonad NEUROSECRETORY CELLS e.g. supraoptic nuclei of hypothalamus •SECRETED INTO BLOOD (free or bound) •LOW CIRCULATING TITRES (e.g. insulin 5 X 10-12 M) •SHORT BIOLOGICAL HALF-LIFE e.g. insulin 5-8 minutes, testosterone 1 hour, FSH 3 hours, thyroxine 6 days •PLASMA CLEARANCE BY: TARGET CELL UPTAKE ENZYMATIC DEGRADATION (liver) URINARY EXCRETION STRUCTURAL CLASSIFICATION OF HORMONES 1. PEPTIDES & PROTEINS 3 >200 a.a. peptide hormones protein hormones (e.g. insulin) 2. AMINES thyroid hormones catecholamines (e.g. epinephrine) tyrosine precursor small, H20-soluble 3. STEROIDS adrenal cortical hormones (e.g. cortisol) gonadal hormones (e.g. estrogen, testosterone) cyclic hydrocarbon derivatives cholesterol precursor lipid soluble 4. EICOSENOIDS (autocrine, paracrine) prostaglandins cyclic unsaturated fatty acids Peptide/Protein Hormones 2-200 amino acids long Synthesized on the rough ER Often as larger preprohormones Stored in vesicles Prohormones Secreted by exocytosis Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Peptide/Protein Hormones Hydrophilic Soluble in aqueous solutions Travel to target cell dissolved in extracellular fluid Bind to transmembrane receptors Signal transduction Rapid effects on target cell Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Synthesis & Secretion of Peptide Hormones Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.4 Synthesis & Secretion of AVP Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.5 Transmembrane Receptor Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.6 Steroid Hormones Derived from cholesterol Synthesized by smooth ER or mitochondria Three classes of steroid hormones Mineralocorticoids Electrolyte balance Glucocorticoides Stress hormones Reproductive hormones Regulate sex-specific characteristics Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Synthesis of Steroid Hormones Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.7 Steroid Hormones Hydrophobic Can diffuse through plasma membrane Cannot be stored in the cell Must be synthesized on demand Transported to target cell by carrier proteins Example: albumin Bind to intracellular or transmembrane receptors Slow effects on target cell (gene transcription) Stress hormone cortisol has rapid non-genomic effects Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Steroid Hormones Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.8 Amine Hormones Chemicals that possess amine group (–NH2) Example: acetylcholine, catecholamines (dopamine, norepinephrine, epinephrine), serotonin, melatonin, histamine, thyroid hormones Sometimes called biogenic amines Some true hormones, some neurotransmitters, some both Most hydrophilic Thyroid hormones are hydrophobic Diverse effects Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Other Chemical Messengers Eicosanoids Most act as paracrines Hydrophobic Often involved in inflammation and pain Example: prostaglandins, leukotrienes Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.10 Other Chemical Messengers Gases Most act as paracrines Example: nitric oxide (NO), carbon monoxide Purines Function as neuromodulators and paracrines Example: adenosine, AMP, ATP, GTP Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Communication to the Target Cell Receptors on target cell Hydrophilic messengers bind to transmembrane receptor Hydrophobic messengers bind to intracellular receptors Ligand Chemical messenger that can bind to a specific receptor Receptor changes shape when ligand binds Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Ligand-Receptor Interactions Ligand-receptor interactions are specific Only the correctly shaped ligand (natural ligand) can bind to the receptor Ligand mimics Agonists – activate receptors Antagonists – block receptors Many ligand mimics act as drugs or poisons Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings BINDING OF HORMONE TO CELLULAR RECEPTOR PRECEDES BIOLOGICAL RESPONSE OF TARGET CELL depends on: 3D structure of hormone complementary structure of receptor unique molecular shape discriminated exclusively by specific receptor Fig.3.11 Ligand-receptor interactions Ligand-Receptor Binding L + R L-R Formation of L-R complex causes response More free ligand (L) or receptors (R) will increase the response Law of mass action Receptors can become saturated at high L Response is maximal Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Ligand-Receptor Binding Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.12 Changes in Number of Receptors Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.13a Ligand-Receptor Dynamics Affinity of receptor for ligand affects number of L-R complexes Higher affinity constant (Ka) response Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.13b Changes in Number of Receptors Number of receptors affects number of L-R complexes More receptors L-R complexes response Target cells can alter receptor number Down-regulation Target cell decreases the number of receptors Often due to high concentration ligand Up-regulation Target cell increases the number of receptors Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Fig. 3.1 Overview of cell signaling NEURAL SIGNALING Neuron -neurotransmitter released into synaptic cleft (e.g. Ach) NEUROENDOCRINE SIGNALING Neurosecretory cell – specialized neuron; hormone released into blood stream (e.g. oxytocin) ENDOCRINE SIGNALING Non-neuronal; hormone released into blood stream (e.g. insulin, testosterone) Cells show morphological polarity ENDOCRINE SIGNALING Signal Transduction Pathways Convert the change in receptor shape to an intracellular response Four components Receiver Ligand binding region of receptor Transducer Conformational change of the receptor Amplifier Increase number of molecules affected by signal Responder Molecular functions that change in response to signal Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Signal transduction pathways Amplification by signal transduction pathways Fig. 3.15 Types of Receptors Intracellular Bind to hydrophobic ligands Ligand-gated ion channels Lead to changes in membrane potential Receptor-enzymes Lead to changes in intracellular enzyme activity G-protein-coupled Activation of membrane-bound G-proteins Lead to changes in cell activities Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Types of Receptors Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.16 Intracellular Receptors Ligand diffuses across cell membrane Binds to receptor in cytoplasm or nucleus L-R complex binds to specific DNA sequences Regulates the transcription of target genes increases or decreases production of specific mRNA Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Intracellular Receptors Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.17 Ligand-Gated Ion Channels Ligand binds to transmembrane receptor Receptor changes shape opening a channel Ions diffuse across membrane Ions move “down” their electrochemical gradient Movement of ions changes membrane potential Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Ligand-Gated Ion Channels Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.19 Receptor Enzymes Ligand binds to transmembrane receptor Catalytic domain of receptor starts a phosphorylation cascade Phosphorylation of specific intracellular proteins Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Receptor Enzymes Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.20 G-Protein-Coupled Receptors Ligand binds to transmembrane receptor Receptor interacts with intracellular G-proteins Named for their ability to bind guanosine nucleotides Subunits of G-protein dissociate Some subunits activate ion channels Changes in membrane potential Changes in intracellular ion concentrations Some subunits activate amplifier enzymes Formation of second messengers Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings G-Protein-Coupled Receptors Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.25 Cyclic-AMP Signaling Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Figure 3.27 Second Messengers Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Table 3.3 Interaction Among Transduction Pathways Cells have receptors for different ligands Different ligands activate different transduction pathways Response of the cell depends upon the complex interaction of signaling pathways Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Regulation of Cell Signaling Cell signaling is important for regulation of physiological processes Components of biological control systems Sensor Detects the level of a regulated variable Sends signal to an integrating center Integrating center Evaluates input from sensor Sends signal to effector Effector Target tissue that responds to signal from integrating center Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings Regulation of Cell Signaling Set Point The value of the variable that the body is trying to maintain Feedback loops Positive Output of effector amplifies variable away from the set point Positive feedback loops are not common in physiological systems Negative Output of effector brings variable back to the set point Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings