INTRODUCTION PART 1

1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signaltransduction INTRODUCTIONPART 1

3. History 4 000 • The earliest scientific paper recorded in the MEDLINE database as containing the specific term signal transduction within its text was published in 1972. • Research papers directly addressing signal transduction processes began to appear in large numbers in the scientific literature in the late 1980s and early 1990s. 3 500 3 000 2 500 Number of papers published 2 000 1 500 1 000 500 0 1977 1982 1987 1992 1997 2002 2007 Year

4. Signal transduction • Signal transduction comes from the verb to 'transduce' meaning to 'lead across' • In biology signal transduction is the process by which an extracellular signaling molecule activates a membrane receptor that in turn alters intracellular molecules to create a response • Sensing of both the external and internal environments at the cellular level relies on signal transduction

5. Cell communication pathways • The cells that are communicating might be close toeachother or far apart: • Local regulator:cytokines, chemokines • Neurotransmission: Acetylcholine • Hormone: steroid and peptide • Cells can also communicate through direct contact: • Through a cell junction that allows cytoplasmic continuity • Adhesion molecules

6. Cell communication pathways Cytokine producingcell Target cell Inducing stimulus Autocrineaction Cytokine producing cell Cytokine gene Cytokine producing cell Paracrineaction Cytokine Nearby cell Receptor Endocrineaction Signal Target cell Gene activation Circulation Distant cell Biological effects

7. Mechanisms of cytokine action Cytokine producing cell Target cell Effect Starting a cascade Activated Th cells Activation Proliferation Differentiation Pleiotropy A cytokine induces different effects on different target cells B cell Proliferation IL-4 INF-g Activated Th cells Thymocyte Macrophage Proliferation Mast cell Redundancy The action of more cytokine on the target cell is similar Proliferation B cell IL-2 IL-4 IL-5 Activated Th cells IL-12 Synergy The effect of two cytokines is stronger than their additive effects Induces class switch to IgE IL-4 + IL-5 Activated Th cells Activated Th cells B cell Antagonism One cytokine inhibits the effects of another cytokine INF-g Blocks class switch to IgE induced by IL-4 B cell INF-g, TNF, IL-2 and other cytokines IL-4 Activated Th cells

8. Extracellular signaling molecules • Hormones (e.g., melatonin) • Growth factors (e.g., epidermal growth factor) • Extracellular matrix components (e.g., fibronectin) • Cytokines (e.g., interferon-g) • Chemokines (e.g., RANTES) • Neurotransmitters (e.g., acetylcholine, neuropeptides: endorphin, small molecules: serotonine, dopamine) • Neurotrophins (e.g., nerve growth factor) • Active oxygen species and other electronically-activated compounds

9. Three stages of cell signaling • Reception • Binding of messengers (ligand) to the receptors • Receptor activation, changes in conformation, triggers a cascade • Transduction • Activation of other proteins through protein phosphorylation: • Protein kinase • Protein phosphatase • Second messengers: • Cyclic AMP • Calcium ions/Inositol Triphosphate • Response

10. Characteristics of the response • Eventually, the signal creates a change in the cell, either in the expression of the DNA in the nucleus or in the activity of enzymes in the cytoplasm, rearrenging the cytoskeleton etc. • These processes can take milliseconds (for ion flux), minutes (for protein- and lipid-mediated kinase cascades), hours, or days (for gene expression). • There is usually an amplificationof the signal - one hormone can elicit the response of over 108 molecules • Many disease processes, such as diabetes, heart disease, autoimmunity, and cancer arise from defects in signal transduction pathways, further highlighting the critical importance of signal transduction to biology, as well as medicine.

11. Main types of receptors Apolar signal Polar signal Outside of cell Cell membrane Cytoplasm Membrane bound receptor Receptor Inside of cell

12. Types of cell-surface receptors • Ligand-gated ion channels: e.g. acetylcholine receptor • G-protein-linked receptors: guanyl nucleotide binding proteins (G proteins) act as molecular switches; active when GTP is bound, inactive with GDP due to action of intrinsic GTPase – muscarinicAchR • Enzyme-linked receptors: e.g. insulin receptor, T cell receptor • Integrins • Toll-like receptors

13. Ligand-gated ion channels Ions Signal molecule Plasmamembrane Cytoplasm

14. 7-Transmembrane receptors Signal molecule g a b g a b GTP GTP Enzyme Enzyme Enzyme g a b GDP Activatedenzyme G-protein Activated G-protein

15. Mechanism of neurotransmission • Synaptic vesicles contain a neurotransmitter (NT) and release it when their membranes fuse with the outer cell membrane • Neurotransmitter molecules cross the synaptic cleft and bind to receptors known as ligand-gated ion channels (LGICs) and G-protein–coupled receptors (GPCRs) on the postsynaptic neuron • GPCRs on the presynaptic neuron’s axon terminal alter the function of voltage-gated ion channels and modulate neurotransmitter release • Neurotransmitter transporters remove neurotransmitter molecules from the synaptic cleft so that they can be repackaged into vesicles

16. Synapse between two neurons - neurotransmission Presynaptic neuron (axon terminal) Synaptic vesicles NT transporter Voltage-gated sodium channel + Neurotransmitter molecule Ligand-gated ion channel (direct excitation or inhibition) Postsynaptic neuron GPCR (modulatory) +

17. Two types of enzyme receptors Dimer of signal molecule Inactive catalytic domain Active catalytic domain Signal molecule Enzyme Activated enzyme