aVLFZ041 Selected lectures from Physiology1 Receptors: key structures in cell signaling Tibor Stračina stracina@med.muni.cz aVLFZ041 Selected lectures from Physiology3 Signal transduction in multicellular organism ̶ Neuronal signaling ̶ Humoral signaling aVLFZ041 Selected lectures from Physiology4 Cellular signaling signal transduction response https://www.cellsignal.com/contents/science-cst-pathways-cellular-metabolism/insulin-receptor-signaling/pathways-irs aVLFZ041 Selected lectures from Physiology5 Cellular signaling signal transduction response Receptors https://www.cellsignal.com/contents/science-cst-pathways-cellular-metabolism/insulin-receptor-signaling/pathways-irs aVLFZ041 Selected lectures from Physiology6 Receptors ̶ Protein-based structures ̶ Receive and transduce signals ̶ Integrated in signaling pathways aVLFZ041 Selected lectures from Physiology7 Classification ̶ Location: ̶ Intracellular ̶ Cell surface ̶ Function ̶ Ionotropic = ligand-gated ion channels ̶ G protein-coupled ̶ Enzyme-linked Tyrosine kinases Histidine kinases aVLFZ041 Selected lectures from Physiology8 Intracellular vs. cell-surface receptors aVLFZ041 Selected lectures from Physiology9 Ionotropic receptors ̶ Ligand-gated ion channels ̶ Direct change of membrane voltage and/or intracellular concentration of the ion aVLFZ041 Selected lectures from Physiology10 Metabotropic receptors ̶ Production of second messenger ̶ G protein-coupled receptors ̶ Enzyme-linked receptors ̶ Receptor Tyrosine kinases ̶ Receptor Histidine kinases aVLFZ041 Selected lectures from Physiology11 G protein-coupled receptors ̶ Production of second messenger: cAMP, cGMP, DAG, IP3, Ca2+ ̶ Gs ̶ Gi ̶ Gq https://www.khanacademy.org/science/biology/cell-signaling/mechanisms-of-cell-signaling/a/signal-perception aVLFZ041 Selected lectures from Physiology12 Enzyme-linked receptors Receptor tyrosine kinases ̶ Tyrosine kinase activity phosphorilation of enzymes/other proteins https://ars.els-cdn.com/content/image/3-s2.0-B9780124059269000046-f04-04-9780124059269.jpg?_ aVLFZ041 Selected lectures from Physiology13 Regulation of receptor response Down-regulation ̶ Decrease of number and/or sensitivity of the receptors due to increased ligand stimulation ̶ Desensitisation ̶ Internalisation aVLFZ041 Selected lectures from Physiology14 Regulation of receptor response Up-regulation ̶ Increase of number and/or sensitivity of the receptors due to decreased ligand stimulation ̶ (Re)sensitisation ̶ Externalisation ̶ Synthesis de novo aVLFZ041 Selected lectures from Physiology15 Receptor families ̶ Classification according to ligand(s) aVLFZ041 Selected lectures from Physiology16 Adrenergic receptors ̶ G protein-coupled receptors ̶ Subtypes: ̶ Alpha: α1 (Gq) – DAG+IP3; smooth muscle contraction, mydriasis α2 (Gi) – cAMP; platelet activation ̶ Beta (Gs) - cAMP β1 – heart (SA node) β2 – smooth muscle relaxation (bronchodilation) β3 – lipolysis, urination aVLFZ041 Selected lectures from Physiology17 Acetylcholine (cholinergic) receptors ̶ M type = Muscarinic acetylcholine receptors ̶ Metabotropic receptors – G-protein coupled receptors ̶ Subtypes M1 – CNS, autonomic ganglia, salivary glands, stomach M2 – heart (SA node, atria, AV node), CNS M3 – smooth muscle (e.g. vessels, bronchi), endocrine+exocrine glands, GIT, eyes, CNS M4+M5 – CNS ̶ N type = Nicotinic acetylcholine receptors ̶ Ionotropic receptors – ligand-gated ion channels ̶ Subtypes (according to subunits) Nm – „muscular“ type – neuromuscular junction Nn – „neuronal“ type – autonomic ganglia, adrenal medulla aVLFZ041 Selected lectures from Physiology18 Insulin receptor ̶ ligands: insulin, IGF-I, IGF-II ̶ 2 subunits ̶ tyrosine kinase activity https://www.cellsignal.com/contents/science-cst-pathways-cellular-metabolism/insulin-receptor- signaling/pathways-irs aVLFZ041 Selected lectures from Physiology19 Vascular endothelial growth factor (VEGF) receptors ̶ Membrane (mbVEGFR) or soluble (sVEGFR) receptors ̶ Three main subtypes: VEGFR-1, VEGFR-2, VEGFR-3 ̶ Tyrosine kinase activity ̶ Vasculogenesis, angiogenesis aVLFZ041 Selected lectures from Physiology20 Inositol-tris-phosphate (IP3) receptors ̶ Intracellular receptors - endoplasmic reticulum, mitochondria ̶ Types: IP3R1, IP3R2, IP3R3 ̶ Function: ligand-gated Ca2+ channels ̶ Dimerisation and proteinprotein interactions aVLFZ041 Selected lectures from Physiology21 Sigma receptors Sigma receptors Sigma receptor type 2 Sigma receptor type 3 (?) Sigma receptor type 1 • well-characterized • molecular chaperone • Ca2+ handling modulation • various protein-protein interactions • motor control • over-expressed in various types of tumor cells • less-known • immune system aVLFZ041 Selected lectures from Physiology22 Sigma 1 R Su et al., 2016. Trends Pharmacol Sci. 2016; 37(4): 262–278. doi:10.1016/j.tips.2016.01.003 aVLFZ041 Selected lectures from Physiology23 Take home messege Receptors are ̶ crucial structures in cell signaling ̶ important in pathophysiology of many diseases ̶ targets of pharmacotherapy 24 The presentation is copyrighted work created by employees of Masaryk University. Any unauthorised reproduction or distribution of the presentation or individual slides is against the law.