4BBY1030 L12.pdf

Faculty of Life Sciences and Medicine 10th/11th Nov 2022 Dr Suba Poopalasundaram (Dr Clemens Kiecker) Neuroscience Education 4BBY1030 Cell Biology and Neuroscience Lecture 14 Cell signalling Multicellularity requires communication Grow! Differentiate! Store/mobilise energy! Divide! Development Homeo...

Faculty of Life Sciences and Medicine 10th/11th Nov 2022 Dr Suba Poopalasundaram (Dr Clemens Kiecker) Neuroscience Education 4BBY1030 Cell Biology and Neuroscience Lecture 14 Cell signalling Multicellularity requires communication Grow! Differentiate! Store/mobilise energy! Divide! Development Homeostasis Immune defence Communication gone wrong à cancer and other disorders Move! Die! Secrete! Dr Clemens Kiecker L14: Cell signalling 2 Different modes of intercellular communication … and autocrine Dr Clemens Kiecker L14: Cell signalling 3 Examples of signalling factors Hormones (eg. oestradiol, testosterone etc.) Growth factors (eg. Epidermal Growth Factor (EGF)) Metabolic regulators (eg. insulin, glucagon and adrenaline) Neurotransmitters (acetylcholine, glutamate and GABA) Migratory cues (Platelet-Derived Growth Factor (PDGF)) Cell death factors (eg. Tumour Necrosis Factor (TNF)) Developmental patterning factors (eg. Sonic hedgehog (SHH)) Dr Clemens Kiecker L14: Cell signalling Receptors Bind ligands with high selectivity and high affinity Dr Clemens Kiecker L14: Cell signalling 5 Major membrane receptor families Ion channels (eg. nicotinic acetylcholine receptor) G protein-coupled receptors (GPCRs; eg. adrenaline receptor) Enzymes (mostly protein kinases; eg. EGF receptor) Dr Clemens Kiecker L14: Cell signalling G protein-coupled receptors (GPCRs) Dr Clemens Kiecker L14: Cell signalling Eg. b-adrenergic receptor - adrenaline 7 GPCR signalling at the membrane 1. 2. 3. 4. 5. 6. 7. Signal binds to receptor Heterotrimeric G protein associates with receptor (Ga-GDP) GDP/GTP exchange G protein dissociates into Ga-GTP and Gbg subunits Ga-GTP activates effector enzyme (adenylyl cyclase) Effector enzyme produces second messenger (cAMP) Ga subunit hydrolyses GTP to GDP, Gabg complex re-associates, signal terminates Remember: the A1 subunit of cholera toxin stimulates Gsa in gut epithelial cells (Lecture 6) Dr Clemens Kiecker L14: Cell signalling 8 cAMP as a second messenger Structure of ATP Inactivation by hydrolysis Dr Clemens Kiecker L14: Cell signalling 9 cAMP activates protein kinase A (PKA) Dr Clemens Kiecker L14: Cell signalling 10 Protein kinases execute signalling switches Dr Clemens Kiecker L14: Cell signalling 11 Adrenalin triggers ‘fight or flight’ response in muscle cells Dr Clemens Kiecker L14: Cell signalling 12 Activation of protein kinase C (PKC) [Ca2+] = 10-3 M [Ca2+] = 10-7 M [Ca2+] = 10-3 M Dr Clemens Kiecker L14: Cell signalling 13 One ligand, different pathways and effects Receptor G protein Effector enzyme 2nd messenger Effect b-adrenergic Gs Adenylyl cyclase cAMP Gluconeogenesis, lipolysis a1-adrenergic Gq Phospholipase C DAG, IP3 à Ca2+ Smooth muscle contraction (vasoconstriction) Dr Clemens Kiecker L14: Cell signalling 14 One ligand, different pathways and effects Dr Clemens Kiecker L14: Cell signalling 15 Receptor tyrosine kinase pathways EGF (FGF…) Protein kinase (Tyr) small (monomeric) GTPase Protein kinases (Ser/Thr) Proliferation… Dr Clemens Kiecker L14: Cell signalling 16 Multiple signalling pathways and their effects Ligand Receptor Effector/2nd messenger Effect Adrenalin GPCR (b, a1) cAMP, DAG, IP3, Ca2+ Glucose mobilisation Acetylcholine Nicotinic AChR (ion channel) Muscarinic AChR (GPCR) Na+ influx Depolarisation EGF, FGF, … Receptor tyrosine kinases Ras-Raf-MAPK Proliferation TGFb, BMPs TGFb receptor (Ser/Thr kinases) Smad proteins Differentiation, cell death, proliferation Hedgehog Patched + Smoothened (GPCR) Gli proteins Cell fate specification in development, proliferation Light (retinol) Opsins Transducin (G protein), Closing of ion channels, decreases cGMP hyperpolarisation Dr Clemens Kiecker L14: Cell signalling 17