Cellular Communication 1 2024.pdf

ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Cellular Biology & Homeostasis CELLULAR COMMUNICATION Part 1 VP 2024 Clara Camargo, DVM ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE LEARNING OBJECTIVES 1. Know cell signaling terminology 2. Understand basics and general features of cell-cell communicat...

ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Cellular Biology & Homeostasis CELLULAR COMMUNICATION Part 1 VP 2024 Clara Camargo, DVM ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE LEARNING OBJECTIVES 1. Know cell signaling terminology 2. Understand basics and general features of cell-cell communication 3. Understand ligands/first messengers, give some examples 4. Describe the types of signal receptors 5. Understand what are second messengers and list the main classes 6. Understand what are molecular switches and how they affect proteins/enzymes ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE SIMPLE INTRACELLULAR SIGNALING PATHWAY 1 Signal = information 2 Signal detection = specific receptor 3 4 Transduction and information conversion 5 Cellular response, involving a chemical process ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE SIMPLE INTRACELLULAR SIGNALING PATHWAY SIGNAL (LIGAND) RECEPTOR PROTEIN Conversion of information into a chemical change:  SIGNAL TRANSDUCTION INTRACELLULAR SIGNALING PROTEINS Universal Property of Living Cells! METABOLIC ENZYME ALTERED METABOLISM TRANSCRIPTION REGULATORY PROTEIN ALTERED GENE EXPRESSION CYTOSKELETON PROTEIN ALTERED CELL SHAPE OR MOVEMENT EFFECTOR PROTEINS CELLULAR RESPONSE ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE SIGNALING PATHWAY Chain of sequential molecular interactions Multiple sites for regulation and for therapeutic drug action The elements of chemical-signaling pathways are often highly conserved, the same molecules or same basic types of molecules are used in a wide variety of different stimulus-response pathways ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Signal - Response Target cells use different mechanisms to adjust the ways in which they respond to extracellular signals The speed of a response depends on the turnover of signaling molecules  allosteric change or  gene expression Negative feedback loop – output inhibits its own production Positive feedback loop – output stimulates its own production  Can trigger all or none response (gradually increasing concentration of an extracellular signal) A type of response that may be either complete and of full intensity or totally absent, depending on the strength of the stimulus; there is no partial response. For example, a nerve cell is either stimulated to transmit a complete nervous impulse or else it remains in its resting state ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE SIGNAL TRANSDUCTION – General Properties ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE SIGNAL TRANSDUCTION – General Properties Signal transductions are highly specific and extremely sensitive! (a) Specificity: Achieved by precise molecular complementarity between signal and receptor molecules, In multicellular organisms: specific receptors are present in specific cell types II. Cooperativity  Small changes in ligand concentration cause large changes in receptor activation III. Amplification by enzyme cascades  Enzyme once activated catalyzes activation of many molecules of a second enzyme, each of (b) Sensitivity: I. Affinity  Described by dissociation constant Kd  Receptor detects picomolar concentrations of signal molecule which activates many molecules of third enzyme, and so on  Can produce amplifications of several orders of magnitude ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE SIGNAL TRANSDUCTION – General Properties (c) Desensitization (adaptation) Cells can adjust their sensitivity to a signal (d) Integration Ability of a system to receive multiple signals and produce unified and appropriate response Continuous presence of a signal can cause desensitization of the receptor system, decreasing the cell response to that level of stimulus Each cell type is programmed to respond to specific combinations of extracellular signals If stimulus falls below threshold the receptors can be reactivated Each cell type displays a set of receptors that enables it Enables cells to respond to changes in the to respond to a corresponding set of signal molecules concentration of an extracellular signal molecule over produced by other cells a wide range of signal concentrations ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE SOME SIGNALS TO WHICH CELLS RESPOND Antigens Cell surface glycoproteins/oligosaccharides Developmental signals Extracellular matrix components Growth factors Hormones Hydrophilic Lipophilic ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE SOME SIGNALS TO WHICH CELLS RESPOND Mechanical touch (mechanotransduction) Light (phototransduction) Osmolarity Neurotransmitters Nutrients Odorants Tastants Pheromones ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE CELL SIGNALING MECHANISMS Despite the many different types of biological signals, there is a remarkable degree of conservation of signaling mechanisms during evolution!  1000s of different types of biological signals and different responses caused by these signals the machinery for transducing these signals is built from about 10 basic types of protein components We will study some examples of the major classes of signaling mechanisms and how they are integrated in specific biological functions (transmission of nerve signals, responses to hormones and growth factors, etc.) ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE LIGANDS From the Latin word ligare, meaning “to bind” Are not metabolized to useful products Are not intermediates in any cellular activity Have no enzymatic properties Their only function is to change the properties of the receptor  The binding of a ligand with receptor results in a cellular effect → changes in that cell (altering gene transcription or translation, changing cell morphology, stimulating secretion of a molecule…) ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE LIGANDS In protein-ligand binding → the ligand is usually a molecule which produces a signal by binding to a site on a target receptor (i.e., an enzyme, membrane protein/receptor) In DNA-ligand binding → the ligand can be a small molecule, ion, or protein which binds to the DNA double helix (i.e., bind to epigenetic tags) Massive project maps DNA tags that define each cell's identity FYI Tally of "epigenetic" marks can shed light on disease and development Extracellular signal molecules are ligands that can act over short or long distances ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE LIGANDS (FIRST MESSENGERS) Can originate from different types of molecules Proteins Small peptides Amino acids Nucleotides Steroids Retinoids Fatty acid derivatives EX: Hormones, growth factors, extracellular matrix components and neurotransmitters ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE AGONISTS AND ANTAGONISTS Agonist: structural analogs to specific ligands that bind to a receptor and mimic the effects of its natural ligand Antagonist: analogs that bind to the receptor without triggering the normal effect, and thus block the effects of agonists, including the biological ligand Sometimes the affinity of the synthetic agonist or antagonist for the receptor is greater than that of the natural agonist/antagonist ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE LIGANDS (FIRST MESSENGERS) Neurotransmitters They transmit signals across a synapse Endogenous chemicals that enable neurotransmission From one neuron to another target neuron From neuron to muscle cells From neuron to gland cells ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Amino acids: GABA (γ-aminobutyric acid), glutamate NEUROTRANSMITTERS Amines: acetylcholine, serotonin Catecholamines: dopamine, norepinephrine, epinephrine Peptides: endorphins and endogenous opioids (leu-encephalin, met-encephalin, β-endorphin) Atypical (nontraditional): Gases (NO, CO); Endocannabinoids FYI ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE CELL SIGNALING – Can be mechanical or biochemical Biochemical signaling: 1. Intracrine: signals are produced by target cell and stay within this cell (i.e., immune cells growth factor) 3. Paracrine: signals target cells nearby the emitting cell (i.e., neurotransmitters, skin cell's local allergic reaction) 2. Autocrine: signals are produced by the target cell, are secreted, and affect the target cell itself via receptors (i.e., immune cells T lymphocytes) 4. Endocrine: signals target distant cell, via hormones that are released into the bloodstream (i.e.,cortisol, insulin, glucagon, progesterone) ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE RECEPTORS and EFFECTOR PROTEINS A receptor is a protein molecule that receives chemical signals from outside or inside of the cell Effectors proteins elicit cellular responses to signaling molecules The binding of a ligand (signal) activates the receptor which in turn activates intracellular signaling pathways/systems  Intracellular signal proteins process the signal and distribute it to specific intracellular targets (effector proteins) if the cellular response to a particular signaling molecule is shape change, the effector proteins would be enzymes that remodel the cytoskeleton ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE RECEPTORS SPECIFICITY - LIGAND VERSATILITY LIGANDS can exhibit binding versatility, RECEPTORS display high ligand binding to different types of receptors specificity  Different cell types may have different sets of receptors for the same ligand, each of which induces a different response  The same receptor may occur on various cell types  Binding to the same ligand may trigger a different response in each type of cell ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE FYI RECEPTORS SPECIFICITY - LIGAND VERSATILITY Cholinergic receptors: ligand is Acetylcholine Adrenergic receptors: ligands are Catecholamines (dopamine, norepinephrine and epinephrine) ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE RECEPTOR LOCATIONS A. CELL SURFACE Hydrophilic signal molecules B. INTRACELLULAR Cytoplasm Nucleus – Hydrophobic signal molecules ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE CELL SURFACE RECEPTORS 1. Metabotropic receptor: Membrane receptor of eukaryotic cells that acts through second messenger system Initiates metabolic steps (helping cell activity modulation) Examples: G-protein coupled receptors ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE CELL SURFACE RECEPTORS 2. Ionotropic receptor: Example: nicotinic acetylcholine receptors Ligand-gated ion channels Forms ion channel pores → ligand binding activation → opens the channel Excitatory or inhibitory effects depend on equilibrium potential of the ion they pass i.e., Excitatory ionotropic receptors increase sodium permeability across the membrane, whereas inhibitory ionotropic receptors increase chloride permeability. ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE MAJOR TYPES OF CELL SURFACE RECEPTORS 1. G-protein coupled receptors (GPCRs) 2. Enzyme-linked (coupled) receptors Receptor Tyrosine Kinase (RTK) Guanylyl Cyclases Toll-like receptors Cytokine receptors 3. Ligand-gated ion channels 4. Adhesion receptors (Integrins - transmembrane receptors that facilitate cellextracellular matrix adhesion) ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE MAJOR TYPES OF RECEPTORS and SIGNAL TRANSDUCERS From: Lehninger Principles of Biochemistry ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE SECOND MESSENGERS Signaling molecules generated in large amounts in response to receptor activation Diffuse away from their source and spread the signal to other parts of the cell by  Binding to and altering the behavior of selected signaling or effector proteins There are only few second-messenger systems within animal cells ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE SECOND MESSENGERS 1. DIACYLGLYCEROL (DAG) Plasma membrane-associated lipid that can regulate membrane-associated effector proteins 2. INOSITOL 1,4,5-TRISPHOSPHATE (IP3) 3. CYCLIC ADENOSINE MONOPHOSPHATE (cAMP) 4. CALCIUM (Ca2+) water-soluble molecules located within the cytosol ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE MOLECULAR SWITCHES Proteins act as intracellular signaling molecules by activating another protein in a signaling pathway To do this, proteins can switch between active and inactive states, thus acting as molecular switches in response to another signal The external signal flipping the molecular switch could be  a protein kinase, which adds a phosphate group to the protein  a protein phosphatase, which removes phosphate groups When receiving a signal, they switch from an inactive to an active state → Until another process switches them off Very important in the intracellular signaling pathway