Other Receptors FFP1-68 2024 PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-68 Enzyme-linked (, ion-gating) and intracellular receptors Prof Will Ford 337 [email protected]  Learning Outcome...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-68 Enzyme-linked (, ion-gating) and intracellular receptors Prof Will Ford 337 [email protected]  Learning Outcomes 1. Explain the structure and function of ligand- gated 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  Ligand-gated ion channel biophysics amidas & Lynch. Cell Mol Life Sci (2013) 70:1241-1253 Receptor tyrosine kinases (RTK)  Receptor tyrosine kinase FYI structure While often used as an example, the insulin receptor is atypical Epidermal- Platelet- derived growth derived factor receptor growth factor 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 = tyrosine, pY = phosphorylated tyrosine Other arm (SH3 domain) recognises proline on signalling Ras cell signalling Active Ras triggers the activation of numerous cell signalling pathways changes in protein activity and gene expression Cell proliferation More to signalling than Ras -FYI MAPK Tyrosine kinase-linked receptors: Variation on a theme Nuclear exclusion motif hidden, and nuclear localisation motif exposed Nuclear exclusion motif exposed  Tyrosine kinase-linked FYI receptors: 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 receptor types Homodimeric Heterodimeric  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  Homodimeric nuclear receptors agonist Nucle us R R HS HS P P HS HS R P P -ve ↓ gene R R R RE transcription Change R R in protein R expressio +ve ↑ gene n R RE transcription Cellular Cytoplasm respons e  Heterodimeric nuclear receptors Plasma membrane Retinoid X receptor Ligand nucleus Cellular response Protein expression  Nuclear receptors Homodimers Heterodimers Each subunit of dimer binds RXR – common nuclear one repeat receptor monomer Half-sites are inverted Bind direct repeat half-sites repeats (palindromes) Common example: Common example: AGGACA(Nx)TGTCCT TGACCT(Nx)TGACCT TCCTGT ACAGGA ACTGGA ACTGGA Recognition determined by Recognition determined by spacing (Nx or number of spacing base pairs) Receptors for vitamin D, Receptors for progesterone, retinoic acid, 9-Cis retinoic acid glucocorticoids, androgens (binds to RXR), triiodothyronine  Summ ary Ligand-gated G-protein Tyrosine-kinase Intracellular ion channels coupled linked receptor receptor receptor  What we have learned… 1. The concept and nature of receptor signalling 2. The structure and function of tyrosine kinase- linked 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