Metabotropic Receptors Lecture Notes PDF

 Metabotropic receptors Learning Outcomes ================= - Explain the principles of cell signalling and signal transduction - Define metabotropic receptors and G-protein coupled receptors - Explain the structure of G-protein coupled receptors and how this imp...

 Metabotropic receptors Learning Outcomes ================= - Explain the principles of cell signalling and signal transduction - Define metabotropic receptors and G-protein coupled receptors - Explain the structure of G-protein coupled receptors and how this impacts their activity - Explain the actions of a G-protein when a ligand binds - Explain a GPCR signalling transduction Cell signalling and signal transduction ======================================= - One of the most important aspects of modern biochemistry and cell biology - Innate complexity - Enables the following to occur:- - Specialised function of cells - Cell-cell communication - Cells to work together in a co-ordinated fashion - Same principle of signalling exists across diverse range of organisms i.e. animal, plant, bacteria and fungi - Knowledge of cell signalling is critical to understand many disease processes e.g. cancer and diabetes Principles of signal transduction ================================= Types of receptor =================  - Metabotropic - Receptors that mediate their effects by activating a series of metabolic processes, often involving enzyme activation to transduce the signal - 7-Transmembrane G-protein coupled receptors - A general description of the structure of this receptor family and the first stage in the mechanism by which they transduce the chemical signal  Type 2: G protein-coupled receptors =================================== - AKA Metabotropic receptors or 7 transmembrane receptors - Single 400 -- 500 polypeptide chains - Coupled to intracellular effector systems - Via G proteins - Largest family of receptors - 865 are currently known - Most common single target of therapeutic action Structure ========= - 7 transmembrane α-helices -- highly conserved - Extracellular N-terminus - Intracellular C-terminus - Third intracellular loop (i3) highly variable - Both vary greatly in length and sequence **NH 3+** 1. Modification to structure ========================= - Glycosylation - Binds carbohydrate(s) near to the N-terminus - Important for membrane trafficking and membrane insertion - Not important for ligand binding 2. Ligand binding capacity ======================= - Disulphide bond - Forms between cysteines in E2 and E3 loops - Disruption decreases ligand binding 3. Effectiveness of cellular response ================================== - Cysteine in the C-terminal domain - Stabilises interaction between receptor and membrane - Replacing does not affect ligand binding but may reduce G-protein coupling Type 2: G protein-coupled receptors =================================== - Different G-proteins activate different types of effector molecules which can include enzymes and ion channels - E.g. Adenylate cyclase and Phospholipase C - Alpha- subunit confers the subtype - Gs ,Gi ,Gq ,Go or GT [[https://www.mdpi.com/1422-0067/17/5/707]](https://www.mdpi.com/1422-0067/17/5/707)  How does cell signalling trigger the desperate flight of this gazelle? ====================================================================== Fight or flight signalling pathway ================================== - Adrenaline, a hormone, is released by the adrenal gland - Travels through the blood stream to reach its target in muscle or liver cells - Binds to a G protein coupled receptor and initiates a signalling cascade - Resulting in glucose release by the cells leading to increased heart and breathing rates Disease associated with G-proteins - Cholera ============================================ - Excessive signalling - Organism -- *vibrio cholera* - Toxin -- hexameric protein AB~5~ which affects intestinal epithelial cells - Beta subunit attaches to intestinal epithelial cells - Alpha subunits enter cell and modify Gα subunit inhibiting GTPase activity - Adenylate cyclase is permanently on resulting in increase in high concentrations of cAMP - Increase in cAMP concentrations leads to chloride transport into lumen and absorption of Na^+^ leading to water loss - Similar toxin produced by *E.coli* strains