FFP1-68 Receptors STS 2023 (1).pptx

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-68 Enzyme-linked (, ion-gating) and intracellular receptors Prof Steve Safrany 341 [email protected] Learning Outcomes 1. Explain the structure and function of ligandgated ion channels 2. Explain the structure...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-68 Enzyme-linked (, ion-gating) and intracellular receptors Prof Steve Safrany 341 [email protected] Learning Outcomes 1. Explain the structure and function of ligandgated ion channels 2. Explain the structure and function of tyrosine kinase-linked receptors 3. Explain the structure and function of intracellular receptors 4. Outline and compare the signalling cascade for each of these receptor types Four types of receptor – others are available Ligand-gated ion channels Ligand-gated ion channels Structure of ligand-gated ion channels • Ligand-gated ion channels contain receptor subunits around a ‘central pore’ • Receptor is also the ion channel • Allows flow down a concentration gradient • Timescale - ms Ligand-gated ion channel examples Ligand LGICs GPCRs 5-HT 5-HT3 5-HT1, 2, 4, 5, 6, 7 ACh nicotinic muscarinic GABA GABAA GABAB Glutamate* AMPA, Kainate, NMDA mGluR Purinergic P2X P2Y Ligand-gated ion channel regulation desensitised state tends to have higher affinity for the agon Receptor tyrosine kinases (RTK) How do receptor tyrosine kinases ‘receive’ and ‘transmit’ signals? Extracellular domain: responsible for capturing or binding signal (‘ligand’) Single transmembrane helix Intracellular domain: tyrosine phosphorylation pattern drives signal RTK signal transduction Adapter proteins link signalling molecules together, but don’t signal • Growth receptor binding protein 2 (Grb2) is an adapter protein • One ‘arm’ (SH2 domain) of Grb2 recognises a pY on active receptor Binding of RTK-Grb2-SoS to activate Ras • SoS is recruited from the cytoplasm • SoS is a GEF, promoting GDP loss from Ras • Once this happens, Ras binds GTP, making it active • Ras is a G-protein (small GTPase) required to transmit Ras cell signalling Active Ras triggers the activation of numerous cell signalling pathways changes in protein activity and gene expression Cell proliferation Receptor tyrosine kinase structure While often used as an example, the insulin receptor is atypical Tyrosine kinase-linked receptors: Variation on a theme Tyrosine kinase-linked receptors: NO ! Variation on a theme Receptor:ligand stoichiometry varies greatly with TKLRs Five groups: (A) TNF‐alpha and related molecules, (B) IL‐1 family members, (C) TGF‐betas, (D) factors that signal through receptor tyrosine kinases such Nuclear receptors Nuclear receptors • e.g., glucocorticoid receptor • Ligand enters the cells to interact with its receptor • Receptor-ligand translocates to interact directly with nucleus • Changes cell gene Nuclear receptors • Homodimers exist in the cytoplasm • Examples include oestrogen, progesterone, androgen, glucocorticoid, mineralocorticoid receptors • Heterodimers exist in the nucleus already – join with retinoid X receptor. • Examples include thyroid hormone, retinoic acid (vitamin A) • All bind DNA as dimers • Receptors require phosphorylation for activation Nuclear receptors • Homodimers • Heterodimers • Agonist binding causes dissociation of chaperone, dimerisation, phosphorylation and • Agonist binding causes dissociation of corepressor, dimerisation and phosphorylation Nuclear receptors • Homodimers • Heterodimers • Each subunit of dimer binds one repeat • Half-sites are inverted repeats (palindromes) • RXR – common nuclear receptor monomer • Bind direct repeat half-sites • Common example: • Common example: • TGACCT(Nx)TGACCT ACTGGA ACTGGA • AGGACA(Nx)TGTGCT TCCTGT ACAGGA • PR, GR, AR Spacing determines specificity • AGGTCA (N3) TGACCT binds ER - • Recognition determined by spacing • 3bp VDR, 4bp T3R, 5bp RAR Summ ary Ligand-gated ion channels G-protein coupled receptor Tyrosine-kinase linked receptor Intracellular receptor What we have learned… 1. The concept and nature of receptor signalling 2. The structure and function of tyrosine kinaselinked receptors 3. The structure and function of ligand-gated ion channels 4. The structure and function of intracellular receptors 5. The signalling cascade for each of these receptors Further reading and viewing https://www.khanacademy.org/test-prep/ mcat/organ-systems/biosignaling/v/enzy me-linked-receptors https://www.khanacademy.org/test-prep/m cat/organ-systems/biosignaling/v/membra ne-receptors Further reading and viewing Background Science Clinical