M4 L1 - Introduction.docx

M4: L1 - Introduction Wednesday, 11 September 2024 3:00 pm   LOs - Describe the major features of signal transduction pathways - Identify the four origins of a signal - Identify and compare the receptor classes involved in signal transduction - Strategise how a therapy could be d...

M4: L1 - Introduction Wednesday, 11 September 2024 3:00 pm   LOs - Describe the major features of signal transduction pathways - Identify the four origins of a signal - Identify and compare the receptor classes involved in signal transduction - Strategise how a therapy could be developed for a disease by manipulating signal transduction   The main steps in signal transduction -------------------------------------      Origins of a Signal -------------------  - Signalling molecule (hormone) from an endocrine cell which travels through the bloodstream to a distant target cell - Classes of hormones - Peptide hormones - Amino acid hormones - Steroid hormones - can go through PM   - Signalling molecules released from one cell to an adjacent cell - e.g. neuromuscular junction signalling which released Ach from synapse to muscle cells      - Cell secretes signals which acts on the same cell - e.g. growth hormones which causes rapid growth of that cell   - Signalling molecule is embedded in the membrane of signalling cell and attaches to the target cell, causing a response - e.g. antigen presenting cells, notch cells - notch signal on liver cells during development - attaches to adjacent cell so that it differentiates into the same type of cell, presenting the same signal     Receptor classes ---------------- - Three distinct receptor classes involved in signal transduction with distinct properties (all expressed in cell membrane, all response to extracellular signals e.g. hormones and ligands): - G-protein coupled receptors (GPCRs) - Receptor tyrosine kinases (RTKs) - Ligand-gated ion channels (LGICs) - (Proteins that influence second-messenger synthesis - Ion channels - Proteins with intrinsic enzyme activity)        Membrane receptors ------------------ - A receptor is a molecule on the surface of a cell - A receptor recognises a specific type of signal e.g. insulin receptor - A receptor is strategically poised to control what happens inside a cell, producing a specific effect - makes them an excellent drug target     Transduction ------------ - A process by which a chemical or physical signal is transmitted through a cell as a series/cascade of molecule events (dominoes/Rube Goldberg machinery) - Relayed event - Three categories of components - Second messengers - Effector proteins - Ions   - Molecules involved in signal transduction: ------------------------------------------ ### Second messengers involved in transduction - Second messengers are molecules (chemical signals) inside cells that act to transmit signals from a receptor to a target i.e. they are free to move/diffuse in the cell - not attached to membrane - (cause a relay of signals) - Types of second messengers:      ### Effector proteins - Effector proteins are molecules (often, enzymes) inside a cell that further transduce a signal - End result of many signal transductions is the phosphorylation (phos) of dephosphorylation (dephos) of target proteins - Examples: - Kinases - phosphorylate downstream molecules, often results in phosphorylation cascades - Adenylate cyclase (AC) - produces cAMP (secondary messengers) from ATP - Phospholipase - hydrolyses phospholipids   ### Ion channels (part of LGIC) - Ion concentration within a cell play important role in maintaining homeostasis and regulate many physiological functions e.g. neural communication, muscle contraction, cell proliferation, osmotic stability, etc. - Neural - Na+, K+ - Muscle - Ca2+ - Apoptosis - Cl-, K+, Ca2+   Amplification ------------- - How a small amount of signalling molecule can lead to a fast and efficient response - Every step of transduction pathway post-signal binding leads to multiple resulting messengers \--\> ends with a really amplified response    - This graph shows that as ligand conc. increases, fraction of ligand bound to receptors increases and physiological response increases - But, when only 50% of ligands bind to their surface receptor, almost a max physiological response occurs (80%) - So only a small number of ligands need to bind to their receptor to get a large physiological response due to amplification of signal from the small number of ligands   Response and Regulation ----------------------- - If response is not regulated/turned off, overstimulation of signal transduction pathway leading to too much response AND cannot respond to subsequent signals - Once the desired response is achieved, signal transduction pathway needs to be regulated and terminated so system can be sensitive to further stimulation - (details of regulation for diff receptor types discussed in future lectures)     Drug development strategies --------------------------- - If you get a disease - some part of signal transduction has gone wrong (usually, the signal) - e.g. diabetes - not enough insulin signal to cause uptake of glucose into cells - From this, we can design therapies to increase insulin production or provide body with insulin   - If the response is something we want to happen, we can design drugs to target any step of signal transduction to increase the response (inc. signal, reception, transduction, dec. regulation)      - Most of the known human therapeutic drugs target receptors   - Many of these are GPCRs because GPCRs are found in many different system so they are a target by many drugs for many different conditions   Signal Transduction in Drug Discovery Lab -----------------------------------------  - Lab is looking at potential migraine drugs - can be a novel drug or existing drugs used for other conditions   - The CGRP receptor is known to cause increased pain and migraines - so need to inhibit this receptor - Develop a signal which will inhibit this receptor (antagonist) and blocks signalling pathway - prevent signalling molecule from binding and causing a signal transduction pathway, leading to increased pain and migraines - Two types of signals: - Small molecule - Antibody - Effect of drugs can be measured using the pain scale or looking for a change in concentration of the intracellular secondary messenger upon taking the drug - If drug inc. amount of secondary messengers \--\> increased response (pain and migraines) - drug is ineffective     Summary ======= Major features of ST pathways ----------------------------- - Signal - Four major cell communication methods - Endocrine - Paracrine - Autocrine - Plasma-membrane attached signalling - Reception - Transduction - Second messengers - cAMP, IP3, DAG - Ions - Ca2+, Na+, K+, Cl- - Effectors - kinase, AC, phospholipase - Amplification - larger physiological response - Regulation + Response - to turn off   - Three classes of receptors - GPCR - RTK - LGIC - Lab - drug discovery   - LAQ e.g. at start of L2 SIGNAL ------    Cell-surface hormones (main focus of this module)          RECEPTION ---------           TRANSDUCTION ------------       cAMP/cGMP Calcium ion Inositol 1,4,5-triphosphate (IP3)                 Diacylglycerol (DAG)               (don't know how drug works)