aVLFZ041 Selected lectures from Physiology1 Receptors: key structures in cell signaling Tibor Stračina stracina@med.muni.cz aVLFZ041 Selected lectures from Physiology2 Signal transduction in multicellular organism ̶ Humoral signaling ̶ Neuronal signaling aVLFZ041 Selected lectures from Physiology3 Signal transduction in multicellular organism ̶ Humoral signaling ̶ Neuronal signaling ? aVLFZ041 Selected lectures from Physiology4 Signal transduction in multicellular organism ̶ Humoral signaling ̶ Neuronal signaling ? aVLFZ041 Selected lectures from Physiology5 Cellular signaling signal transduction response https://www.cellsignal.com/contents/science-cst-pathways-cellular-metabolism/insulin-receptor-signaling/pathways-irs aVLFZ041 Selected lectures from Physiology6 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 Physiology7 Receptors ̶ Protein-based structures ̶ Receive and transduce signals ̶ Integrated in signaling pathways aVLFZ041 Selected lectures from Physiology8 Classification ̶ Location: ̶ Intracellular ̶ Cell surface ̶ Function ̶ Ionotropic = ligand-gated ion channels ̶ G protein-coupled ̶ Enzyme-linked Tyrosine kinases Histidine kinases aVLFZ041 Selected lectures from Physiology9 Intracellular vs. cell-surface receptors aVLFZ041 Selected lectures from Physiology10 Ionotropic receptors ̶ Ligand-gated ion cahnnels ̶ Direct change of membrane voltage and/or intracellular concentration of the ion aVLFZ041 Selected lectures from Physiology11 Metabotropic receptors ̶ Production of second messenger ̶ G protein-coupled receptors ̶ Enzyme-linked receptors ̶ Receptor Tyrosine kinases ̶ Receptor Histidine kinases aVLFZ041 Selected lectures from Physiology12 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 Physiology13 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 Physiology14 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 Physiology15 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 Physiology16 Receptor families ̶ Classification according to ligand(s) aVLFZ041 Selected lectures from Physiology17 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 Physiology18 Insuline receptors https://www.cellsignal.com/contents/science-cst-pathways-cellular-metabolism/insulin-receptor-signaling/pathways-irs aVLFZ041 Selected lectures from Physiology19 VEGFR ̶ Vascular endothelial growth factor receptor aVLFZ041 Selected lectures from Physiology20 IP3 receptors ̶ Inositol-tris-phosphate receptors 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 Receptors ̶ Crucial structures in cell signaling ̶ Important in pathophysiology of many diseases ̶ Targets of pharmacotherapy