VLFZ041 Vybrané kapitoly z fyziologie1 Receptory: klíčové struktury v buněčné signalizaci Tibor Stračina stracina@med.muni.cz VLFZ041 Vybrané kapitoly z fyziologie3 Signal transduction in multicellular organism ̶ Humoral signaling ̶ Neuronal signaling VLFZ041 Vybrané kapitoly z fyziologie4 Signal transduction in multicellular organism ̶ Humoral signaling ̶ Neuronal signaling ? VLFZ041 Vybrané kapitoly z fyziologie5 Signal transduction in multicellular organism ̶ Humoral signaling ̶ Neuronal signaling ? VLFZ041 Vybrané kapitoly z fyziologie6 Cellular signaling signal transduction response https://www.cellsignal.com/contents/science-cst-pathways-cellular-metabolism/insulin-receptor-signaling/pathways-irs VLFZ041 Vybrané kapitoly z fyziologie7 Cellular signaling signal transduction response Receptors https://www.cellsignal.com/contents/science-cst-pathways-cellular-metabolism/insulin-receptor-signaling/pathways-irs VLFZ041 Vybrané kapitoly z fyziologie8 Receptors ̶ Protein-based structures ̶ Receive and transduce signals ̶ Integrated in signaling pathways VLFZ041 Vybrané kapitoly z fyziologie9 Classification ̶ Location: ̶ Intracellular ̶ Cell surface ̶ Function ̶ Ionotropic = ligand-gated ion channels ̶ G protein-coupled ̶ Enzyme-linked Tyrosine kinases Histidine kinases VLFZ041 Vybrané kapitoly z fyziologie10 Intracellular vs. cell-surface receptors VLFZ041 Vybrané kapitoly z fyziologie11 Ionotropic receptors ̶ Ligand-gated ion channels ̶ Direct change of membrane voltage and/or intracellular concentration of the ion VLFZ041 Vybrané kapitoly z fyziologie12 Metabotropic receptors ̶ Production of second messenger ̶ G protein-coupled receptors ̶ Enzyme-linked receptors ̶ Receptor Tyrosine kinases ̶ Receptor Histidine kinases VLFZ041 Vybrané kapitoly z fyziologie13 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 VLFZ041 Vybrané kapitoly z fyziologie14 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?_ VLFZ041 Vybrané kapitoly z fyziologie15 Regulation of receptor response Down-regulation ̶ Decrease of number and/or sensitivity of the receptors due to increased ligand stimulation ̶ Desensitisation ̶ Internalisation VLFZ041 Vybrané kapitoly z fyziologie16 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 VLFZ041 Vybrané kapitoly z fyziologie17 Receptor families ̶ Classification according to ligand(s) VLFZ041 Vybrané kapitoly z fyziologie18 Adrenergic receptors ̶ G protein-coupled receptors ̶ Ligands: catecholamines ̶ Epinephrine (adrenaline) ̶ Norepinephrine (noradrenaline) ̶ Dopamine VLFZ041 Vybrané kapitoly z fyziologie19 Adrenergic receptors - subtypes ̶ Alpha: ̶ α1 (Gq) – DAG+IP3; smooth muscle contraction, mydriasis ̶ α2 (Gi) – cAMP; platelet activation ̶ Beta (Gs) ̶ β1 – heart (SA node) ̶ β2 – smooth muscle relaxation (bronchodilation) ̶ β3 – lipolysis, urination VLFZ041 Vybrané kapitoly z fyziologie20 Dopamine receptors ̶ G protein-coupled receptors ̶ Ligand: dopamine ̶ Expression: ̶ CNS – neurotransmission, neuromodulation ̶ peripheral (non-)neural tissues VLFZ041 Vybrané kapitoly z fyziologie21 Dopamine receptors - subtypes ̶ D1-like family (Gs): D1, D5 ̶ D2-like family (Gi): D2, D3, D4 ̶ Dimerization ̶ Heterodimers (e.g. D1-D2) ̶ Non-isoreceptor heterodimers (e.g. D2-Adenosine A2R) ̶ Protein interactions VLFZ041 Vybrané kapitoly z fyziologie22 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 VLFZ041 Vybrané kapitoly z fyziologie23 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 VLFZ041 Vybrané kapitoly z fyziologie24 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 VLFZ041 Vybrané kapitoly z fyziologie25 Inositol-tris-phosphate (IP3) receptors ̶ Intracellular receptors - endoplasmic reticulum, mitochondria ̶ Types: IP3R1, IP3R2, IP3R3 ̶ Function: ligand-gated Ca2+ channels ̶ Dimerisation and proteinprotein interactions VLFZ041 Vybrané kapitoly z fyziologie26 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 VLFZ041 Vybrané kapitoly z fyziologie27 Sigma 1 R Su et al., 2016. Trends Pharmacol Sci. 2016; 37(4): 262–278. doi:10.1016/j.tips.2016.01.003 VLFZ041 Vybrané kapitoly z fyziologie28 Take home messege Receptors are ̶ crucial structures in cell signaling ̶ important in pathophysiology of many diseases ̶ targets of pharmacotherapy