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Introduction to Signal Transduction

Introduction to Signal Transduction. Signal transduction. Conversion of information from one form to another In biology, the molecular mechanisms that allow communication and response between cells Involves biochemical reactions Timeframe is milliseconds to seconds.

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Introduction to Signal Transduction

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  1. Introduction to Signal Transduction www.doctorsherwan.com

  2. Signal transduction • Conversion of information from one form to another • In biology, the molecular mechanisms that allow communication and response between cells • Involves biochemical reactions • Timeframe is milliseconds to seconds www.doctorsherwan.com

  3. Multicellularity – a problem of communication • Why do cells need to communicate? • When to grow • When to stop growing • When to die • When to produce products • Breakdown of communication could mean cell death, at best, or cancer, at worst www.doctorsherwan.com

  4. Cells and Their Functions • Production of material for export – e.g. fatty acids, insulin, • Release of glandular products – e.g. adrenaline • Growth – e.g. Wound repair • Movement – e.g. during development • Recruitment to targets – e.g. macrophages to a wound site www.doctorsherwan.com

  5. Events in Signal Transduction • Release of the signal from the source tissue • Travel of the signal • Arrival of signal at target tissue • Binding of signal to proper receptor • Induction of signal event www.doctorsherwan.com

  6. Cell structure is a problem for communication • Membranes • Cellular membrane, nuclear and mitochondrial membranes • Cellular compartments • Nucleus, mitochondria, peroxisomes www.doctorsherwan.com

  7. Cell membrane structure www.doctorsherwan.com

  8. Drug receptor • Each drug requires a target within the body – a receptor • Receptor is a molecule within the body that responds to the drug by binding to it • Three properties for receptors: • Quantitative • Selective • Use agonists or antagonists www.doctorsherwan.com

  9. Drug Receptor Quality - Quantitative • Receptors determine the quantitative relations between dose of a drug and the pharmacological effects • Affinity of the receptor for the drug affects amount of drug • Total number of receptors affects maximal response www.doctorsherwan.com

  10. Drug Receptor Quality - Selective • Receptor shape, through three dimensional structure, charge, and other characteristics, determines which molecules can bind • Affinity – how well the drug binds • Selectivity – how well the drug binds to intended target(s) versus all of the other proteins in the body www.doctorsherwan.com

  11. Drug receptor quality – Agonists and antagonists • Not all drugs have a positive role. Some can displace natural molecules and prevent them from acting • Agonist – acts in a positive way • Antagonist – acts in a negative way, preventing other things from acting www.doctorsherwan.com

  12. Receptor types 9/19/2006 Introduction to Pharmacology 11 www.doctorsherwan.com

  13. Receptor types • Intracellular receptor • Transmembrane, with receptor portion outside and enzyme portion inside • Transmembrane, with receptor portion outside and attached enzyme inside • Transmembrane, with receptor portion outside and activated membrane channel • Transmembrane, with receptor outside and linked enzyme/effector inside www.doctorsherwan.com

  14. Nervous system • Requires: • Rapid communication between tissues (brain to target tissue, and back) • Structure • Long nerve cells separated by small junctions • Signaling: • Depolarization along the fibers • Neurotransmitters between the nerves themselves www.doctorsherwan.com

  15. Nicotinic Acetylcholine Receptor (AChR) www.doctorsherwan.com

  16. Nicotinic Acetylcholine Receptor • Ion channels that open in response to acetylcholine binding • Expressed in the CNS and PNS • Pharmacological agents: • Nicotine – activates the receptor, agonist • Curare – inhibits the receptor, antagonist • Modification of signal • Endocytosis of the receptor • Modification by phosphorylation • This receptor is like number 4 on the figure with the receptors. www.doctorsherwan.com

  17. Signal transduction • Signal transduction events start with recognition of the signal in a target tissue • Receptors are proteins that bind to the signals and begin transducing the signal • Depending on the type of signal, the response can be short and fast, or long and slow. www.doctorsherwan.com

  18. Types of Signaling Molecules • Examples that we will examine in greater depth: • I. Thyroid hormone (like #1) • II. Epinephrine/Adrenaline (like #5) • III. Insulin (not exactly like #3) • IV. Epidermal growth factor (EGF) (not exactly like #3) • Already covered – Acetylcholine receptor (like #4) www.doctorsherwan.com

  19. Receptor types 9/19/2006 Introduction to Pharmacology 18 www.doctorsherwan.com

  20. I. Thyroid hormone • Function: • Increases metabolic rate • sensitivity to adrenaline • Produced by the thyroid gland in the neck • Thyroid hormone is somewhat stable, and the response is long and slow, even after the signal is removed. www.doctorsherwan.com

  21. I. Thyroid hormone • Structure - Lipid soluble hormone, that penetrates the nucleus of the cell to bind to the thyroid hormone receptor(s) (TR) • T4 – thyroxine • T3 – triiodothyronine T3 - triiodothyronine T4 thyroxine www.doctorsherwan.com

  22. I. Thyroid hormone • Chemical properties • lipid soluble • both contain iodine, T3 has one less iodine than T4 • Transport • Flows through the blood, often bound to serum • Can cross the blood brain barrier using special transporter molecules www.doctorsherwan.com

  23. Thyroid hormone receptor (TR) www.doctorsherwan.com

  24. I. Thyroid Hormone • Hypothyroidism • Caused by insufficient production of thyroid hormone • Lack of iodine for thyroid hormone production • Autoimmune disease, others… • Weight gain, impaired memory, fatigue, many other symptoms • Treatments • Synthetic thyroxine (levothyroxine) which substitutes T4 • More stable than T4 www.doctorsherwan.com

  25. I. Thyroid Hormone • Hyperthyroidism • Caused by overproduction of thyroid hormone • Usually Graves’ disease • Weight loss, large appetite, fatigue, sweating, heart problems, etc. • Treatments • Surgery to remove part of thyroid gland • Radioiodine to kill the thyroid gland • Thyrostatic drugs www.doctorsherwan.com

  26. II. Epinephrine (adrenaline) • Function: Fight-or-flight response “energy mobilization”: • Increases pulse rate, blood pressure • Stimulates glycogenolysis and lipolysis • Decreases blood flow to gut • Pre-synthesized in the adrenal medulla, and released into the blood • Binds to receptors in heart, smooth muscle, liver, and adipose www.doctorsherwan.com

  27. II. Epinephrine (adrenaline) • Properties • Synthesized by the adrenal medulla • Both a hormone and neurotransmitter • Fight-or-flight • Stimulation of the locus ceruleus by a novel stimulus • Signal through sensory cortex of brain to thalamus to brain stem • Activation of sympathetic autonomic nervous system • Acetylcholine released from preganglionic sympathetic nerves • Epinephrine released from medulla of adrenal gland www.doctorsherwan.com

  28. Epinephrine (adrenaline) receptor www.doctorsherwan.com

  29. Epinephrine (adrenaline) receptor • There are two main groups of epinephrine receptors • Alpha – nerve terminals • Beta – heart, lung, and adipose tissue • Although each receptor is activated by epinephrine, downstream actions are different depending on the receptor www.doctorsherwan.com

  30. a2-adrenergic receptors • Epinephrine binds • Gi protein is activated • Adenylyl cyclase is inhibited • cAMP levels decrease www.doctorsherwan.com

  31. b-adrenergic receptors • Epinephrine binds • Gs protein is activated • Adenylyl cyclase is activated • cAMP levels increase • cAMP-dependent protein kinase (PKA) is activated • Downstream targets are phosphorylated… www.doctorsherwan.com

  32. Epinephrine receptors www.doctorsherwan.com

  33. Side-note: • Pseudoephedrine • No longer in OTC cold medications because it is a precursor in amphetamine production • Induces release of norepinephrine by displacing it from storage vesicles • Constricts blood vessels in nasal cavities, preventing fluid leakage and reducing symptoms of congestion • Irritability, insomnia, others. • Phenylephrine • Less effective decongestant • Not an amphetamine precursor • Stated less rebound congestion • Rebound congestion • Stimulation of alpha1 receptors in the nose by nasal stimulants • After 5-7 days, more drug, more often is required. Why? www.doctorsherwan.com

  34. III. Insulin • Function: • Stimulates glucose uptake, glycogenesis, protein synthesis, and lipid synthesis • Synthesized in response to sugar in the blood in pancreas • Insulin travels through blood to bind to insulin receptors in target organs in the body • Structure • Insulin is a polypeptide that undergoes post-translational modifications prior to secretion www.doctorsherwan.com

  35. III. Insulin receptor www.doctorsherwan.com

  36. III. Insulin receptor • Insulin binds to the receptor • Insulin receptor autophosphorylates • IRS-1 is phosphorylated • Ras G protein is activated • Ras activates downstream factors • Raf-1 (MAP-KKK), MAPKK, MAPK, S6K, • Protein phosphatase-1 is activated by S6K • S6K (small ribosomal subunit protein 6 kinase) • Dephosphorylates and activates glycogen synthase • Dephosphorylates and inactivates glycogen phosphorylase • Net result: glycogen is synthesized in target cells www.doctorsherwan.com

  37. III. Insulin • Diabetes – persistent hyperglycemia • Injected insulin as treatment • Diet, exercise to reduce blood glucose • Difficult to treat because of the small window of acceptable glucose concentrations in the blood www.doctorsherwan.com

  38. IV. Epidermal growth factor • Function: • Stimulates cell growth in many different cell types (not just epidermis) • Binds to the EGF receptor • Structure • Polypeptide www.doctorsherwan.com

  39. EGF (epidermal growth factor) receptor www.doctorsherwan.com

  40. EGFR • EGF binds to monomeric EGF receptors in the cell membrane • Binding of EGF induces dimerization of the receptor, bringing together intracellular kinase domains • EGFR autophosphorylates • EGFR then phosphorylates other targets within the cell to continue signal transduction events www.doctorsherwan.com

  41. Receptor conclusions: • There are diverse types of receptors: • Intracellular or integral membrane proteins • Monomeric or multimeric • Sometimes there are more than one receptor for a given signal • Example: epinephrine receptors (alpha and beta types) • Receptors signal into the cell through diverse mechanisms www.doctorsherwan.com

  42. Other related topics: • Receptor regulation • Spare receptors • Receptor discovery • Crosstalk www.doctorsherwan.com

  43. Receptor regulation • Protein modification – phosphorylation • Downregulation of the receptor • Internalization • Turnover • ubiquitination • Desensitization • binding of inhibitory proteins www.doctorsherwan.com

  44. Receptor Desensitization Mechanism www.doctorsherwan.com

  45. Spare receptors • Higher receptor to ligand ratio: allows for higher sensitivity • Signal amplification and spare receptors together increase the chance of a signal being successfully transduced • Not all available receptors need to be bound by agonist for a maximal effect www.doctorsherwan.com

  46. Spare receptors www.doctorsherwan.com

  47. Spare receptors • Occurs when you do not need binding of every receptor for a response to occur. www.doctorsherwan.com

  48. Receptor Discovery www.doctorsherwan.com

  49. Crosstalk • Signaling pathways can interact to either upregulate or downregulate one another • For example, the insulin pathway versus the epinephrine pathway • Epinephrine activates beta-adrenergic receptors in muscles, resulting in glycogenolysis • Insulin stimulates the production of glycogen • These pathways work by modulating the receptors or other downstream proteins www.doctorsherwan.com

  50. Second messengers • Second messengers have multiple functions: • Relay signal from initial receptor • Amplify the signal • Relay signal to targets in the cytosol and/or nucleus • Can be multiple targets • Classes of second messengers • Cyclic nucleotides (cAMP and cGMP) • Inositol triphosphate (IP3) and diacylglycerol (DAG) • Calcium ions (Ca2+) • Arachidonic acids www.doctorsherwan.com

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