Brunel University London Introduction to Medical Sciences 1 Building Blocks of Cells PDF

Introduction to Medical Sciences 1 Building Blocks of Cells Part 2 Signal transduction (GPCRs) Copyright © Brunel University London v.3 2024. All rights reserved Building Blocks of Cells Dr Ricardo Carnicer Hijazo 2024 Version 3 Ricardo.CarnicerHijazo@brunel...

Introduction to Medical Sciences 1 Building Blocks of Cells Part 2 Signal transduction (GPCRs) Copyright © Brunel University London v.3 2024. All rights reserved Building Blocks of Cells Dr Ricardo Carnicer Hijazo 2024 Version 3 [email protected] Copyright © Brunel University London v.3 2024. All rights reserved 5  Functions of Membrane Proteins 1. Signal 2. Transport 3. Intercellular Transduction Connections 4. Cell-Cell 5. Cell 6. Enzyme Recognition Attachment Activity Copyright © Brunel University London v.3 2024. All rights reserved 6 1. Signal transduction Signal transduction is the transmission of signals from the cell’s exterior to its interior in order to trigger a response. Ligand Receptor Reception Signal transduction pathways Image by RCH. Content is available under CC BY-SA 3.0 RESPONSE Copyright © Brunel University London v.3 2024. All rights reserved 7 1. Signal transduction A) G protein-coupled receptors - Cyclic AMP signal pathway - Phosphoinositide signal pathway B) Receptor tyrosine kinases - MAP Kinases signal pathway - Phosphoinositide pathway Copyright © Brunel University London v.3 2024. All rights reserved 8 G protein-coupled receptors (GPCRs) Extracellular Receptor structure - Seven transmembrane helices. Receptor - Extracellular binding site for ligands. - Intracellular binding site for G protein. From Cell biology by Thomas D. Pollard. Ed. 2017 Intracellular G protein Copyright © Brunel University London v.3 2024. All rights reserved 9  G protein-coupled receptors (GPCRs) G protein Receptor - Bind Guanine nucleotides (GDP, GTP) - Heterotrimer with 3 subunits. - α subunit: binds GDP in the inactive state. - β subunit: forms stable complex with γ subunit. - γ subunit: attached to membrane by From Cell biology by Thomas D. Pollard. Ed. lipid anchor. 2017 GDP: Guanosine diphosphate Copyright © Brunel University London v.3 2024. All rights reserved 10 G protein-coupled receptors (GPCRs). Receptor Ligands - Hormones. - Neurotransmitters. - Light-sensitive compounds. Image from Cell biology by Thomas D. Pollard. Ed. 2017 Copyright © Brunel University London v.3 2024. All rights reserved 11  GDP: Guanosine diphosphate Activation of GPCRs GTP: Guanosine triphosphate Image from Cell Receptor Receptor biology by Thomas D. Pollard. Ed. 2017 1 2 3 1 Inactive G-protein trimer binds GDP. 2 Ligand binds receptor, G-protein binds GTP. Signal transduction 3 The α subunit and β-ϒ complex are released and activate the next step in the pathway. Copyright © Brunel University London v.3 2024. All rights reserved 12 Deactivation of GPCRs Ligand Receptor Receptor Image from Cell biology by Thomas D. 2 Pollard. Ed. 2017 3 4 1 Inactive G protein binds GDP. 2 Ligand binds receptor, G-protein binds GTP. 3 The α subunit and β-ϒ complex are released and activate the next step. 4 The α subunit hydrolyses GTP into GDP and binds the receptor (inactive state) Copyright © Brunel University London v.3 2024. All rights reserved 13 Signal amplification Receptor Receptor 1 2 3 Signal transduction 14 Copyright © Brunel University London v.3 2024. All rights reserved GPCRs effector molecules 1. Cyclic AMP signal pathway 2. Phosphoinositide signal pathway Copyright © Brunel University London v.3 2024. All rights reserved 15 Cyclic-AMP cascade Low Glucose in blood! Glucagon Glucagon Receptor Adenylyl cyclase ATP Cyclic AMP cAMP: cyclic adenosine monophosphate Image by RCH. Content is RESPONSE available under CC BY-SA 3.0 Copyright © Brunel University London v.3 2024. All rights reserved 16 Cyclic-AMP cascade Glucagon First messenger Glucagon Glucagon Receptor Second messenger Adenylyl cyclase ATP Cyclic AMP Second messengers are intracellular signalling RESPONSE molecules released in response to exposure to extracellular signalling molecules—the first messengers. cAMP: cyclic adenosine monophosphate Copyright © Brunel University London v.3 2024. All rights reserved 17 Cyclic-AMP cascade Low Glucose in blood! Glucagon Glucagon Receptor Adenylyl cyclase ATP Cyclic AMP Protein Kinase A Kinase: a protein that catalyses the transfer RESPONSE of a phosphate group from ATP to a specified molecule. cAMP: cyclic adenosine monophosphate ATP: adenosine triphosphate Copyright © Brunel University London v.3 2024. All rights reserved 18 Cyclic-AMP cascade Low Glucose in blood! Glucagon Glucagon Receptor Adenylyl cyclase ATP Cyclic AMP Protein Kinase A Phosphorylation RESPONSE Glycogen Glucose cAMP: cyclic adenosine monophosphate Copyright © Brunel University London v.3 2024. All rights reserved 19 Cyclic-AMP cascade Low Glucose in blood! Glucagon Signal Glucagon Receptor amplification Adenylyl cyclase ATP Cyclic AMP Protein Kinase A RESPONSE Phosphorylation cAMP: cyclic adenosine monophosphate Glycogen Glucose Copyright © Brunel University London v.3 2024. All rights reserved 20 GPCRs effector molecules 1. Cyclic AMP signal pathway 2. Phosphoinositide signal pathway Copyright © Brunel University London v.3 2024. All rights reserved 21 Phosphoinositide cascade Low blood pressure! Angiotensin II Phospholipase: a protein that Angiotensin II receptor breaks down phospholipids. Phospholipase C PIP2 IP3 + DAG RESPONSE PIP2: phosphatidyl inositol biphosphate IP3: inositol triphosphate DAG: diacylglycerol Image by RCH. Content is available under CC BY-SA 3.0 Copyright © Brunel University London v.3 2024. All rights reserved 22 Phosphoinositide cascade Low blood pressure! Angiotensin II Angiotensin II receptor Phospholipase C Second messengers IP3 + DAG PIP2 RESPONSE PIP2: phosphatidyl inositol biphosphate IP3: inositol triphosphate DAG: diacylglycerol 23 Copyright © Brunel University London v.3 2024. All rights reserved Phosphoinositide cascade Low blood pressure! Angiotensin II Angiotensin II receptor Phospholipase C PIP2 IP3 + DAG Protein Kinase C Phosphorylation RESPONSE Vessel vasoconstriction PIP2: phosphatidyl inositol biphosphate IP3: inositol triphosphate DAG: diacylglycerol Copyright © Brunel University London v.3 2024. All rights reserved 24 GPCRs function - Senses: vision, taste and smell. - Pain. - Behavioural and mood regulation. - Regulation of immune system activity and inflammation. - Autonomic nervous system transmission: blood pressure, heart rate, and digestive processes. - Endocrine system. - Cell proliferation. Copyright © Brunel University London v.3 2024. All rights reserved 25 GPCRs in disease Inhibition of Receptor- Protein G interaction Inhibition of GTPase activity Pertussis toxin, night blindness Cholera toxin, cancer GPCRs are targets for about 50% of drugs currently on the market e.g. mental, metabolic, immunological, respiratory, cardiovascular, inflammatory, senses disorders, and cancer. Copyright © Brunel University London v.3 2024. All rights reserved 26 Harnessing the signalling pathways of GPCRs PPO is used by neuroscientists to control brain circuitry. It inhibits neuronal activity suppressing reward-seeking behaviours. Copyright © Brunel University London v.3 2024. All rights reserved 27 Cyclic AMP cascade (Video) https://www.youtube.com/watch?v=Z7YK9cA1x70 Phosphatidylinositide cascade (Video) https://www.youtube.com/watch?v=2PCexQiCjfI Copyright © Brunel University London v.3 2024. All rights reserved 28 To contact me: [email protected] Copyright © Brunel University London v.3 2024. All rights reserved