2. Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

3. INTRODUCTION PART 1 Tímea Berki and Ferenc Boldizsár Signal transduction Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

4. TÁMOP-4.1.2-08/1/A-2009-0011 History 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. Year Number of papers published 200720021997199219871982197 7 0 500 1 000 1 500 2 000 2 500 3 000 3 500 4 000

5. TÁMOP-4.1.2-08/1/A-2009-0011 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

6. TÁMOP-4.1.2-08/1/A-2009-0011 Cell communication pathways The cells that are communicating might be close to each other 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

7. TÁMOP-4.1.2-08/1/A-2009-0011 Cell communication pathways Inducing stimulus Cytokine producing cell Cytokine Receptor Target cell Biological effects Nearby cell Circulation Distant cell Cytokine producing cell Cytokine producing cell Target cell Autocrine action Paracrine action Endocrine action Cytokinegene Signal Geneactivation

8. TÁMOP-4.1.2-08/1/A-2009-0011 Mechanisms of cytokine actionRedundancy The action of more cytokine on the target cell is similar Synergy The effect of two cytokines is stronger than their additive effects Antagonism One cytokine inhibits the effects of another cytokine Pleiotropy A cytokine induces different effects on different target ce lls Effect Target cell Activation Proliferation Differentiation Proliferation INF-g IL-12 INF-g, TNF, IL-2 and other cytokines IL-4 IL-2 IL-4 IL-5 IL-4 + IL-5 IL-4 INF-g Starting a cascade Cytokine producing cell Proliferation Mast cell B cell ThymocyteActivated Th cells Proliferation B cell Activated Th cells Blocks class switch to IgE induced by IL-4 B cell Activated Th cells Induces class switch to IgE B cell Activated Th cells Macrophage Activated Th cells

9. TÁMOP-4.1.2-08/1/A-2009-0011 Extracellular signaling molecules Hormones (e.g., melatonin) Growth factors (e.g., epidermal growth factor) Extracellular matrix components (e.g., fibronectin) Cytokines (e.g., interferon-  ) 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

10. TÁMOP-4.1.2-08/1/A-2009-0011 Three stages of cell signalingReception Binding of messengers (ligand) to the receptors Receptor activation, changes in conformation, triggers a cascade Transduction Transduction Activation of other proteins through protein phosphorylation: –Protein kinase –Protein phosphatase Second messengers: –Cyclic AMP –Calcium ions/Inositol TriphosphateResponse

11. TÁMOP-4.1.2-08/1/A-2009-0011 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 amplification of the signal - one hormone can elicit the response of over 10 8 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.

12. TÁMOP-4.1.2-08/1/A-2009-0011 Cytoplasm Outside of cell Apolar signal Receptor Polar signal Membrane bound receptor Cell membrane Inside of cell Main types of receptors

13. TÁMOP-4.1.2-08/1/A-2009-0011 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 – muscarinic AchR Enzyme-linked receptors: e.g. insulin receptor, T cell receptor Integrins Toll-like receptors

14. TÁMOP-4.1.2-08/1/A-2009-0011 Ions Signal molecule Cytoplasm Plasma membrane Ligand-gated ion channels

15. TÁMOP-4.1.2-08/1/A-2009-0011GDP    GTP      Enzyme GTP  Signal molecule G-proteinActivated G-protein Activated enzyme 7-Transmembrane receptors

16. TÁMOP-4.1.2-08/1/A-2009-0011 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

17. TÁMOP-4.1.2-08/1/A-2009-0011 Presynaptic neuron (axon terminal) Postsynaptic neuron Neurotransmitter molecule NT transporter Synaptic vesicles Voltage-gated sodium channel GPCR (modulatory ) Ligand-gated ion channel (direct excitation or inhibition) + + Synapse between two neurons - neurotransmission

18. TÁMOP-4.1.2-08/1/A-2009-0011 Enzyme Signal molecule Activated enzyme Dimer of signal molecule Inactive catalytic domain Active catalytic domain Two types of enzyme receptors