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Appendix: Receptor Proteins #           Ligand-gated ion channels 1023 Receptors with intrinsic enzyme function 1026 Receptor tyrosine kinases (RTKs) 1026 Receptor serine/theorine kinases 1028 Receptor-linked guanylyl cyclases 1028 G-protein coupled receptors (GPCRs) 1028 Receptors 1028 Heterotrimeric G-proteins 1035 RGS proteins 1036 Cytokine receptors (Jak/STAT-coupled) 1037 TNF receptor superfamily 1038 IL-1 / toll-like receptors 1039 Nuclear receptors 1040 Channel proteins 1043 Sodium channels 1043 Potassium channels 1044 Voltage-dependent Ca2+-channels 1047 Chloride channels 1048 Cation channels 1049 TRP channels 1049 Cyclic nucleotide-regulated cation channels 1050 Calcium release channels 1050 Water channels 1051 Solute carriers (transporters) 1052 Transport ATPases (ATP-powered pumps) 1058 P-type ATPases 1058 V-type ATPases 1059 F-type ATPases 1060 ABC-transporter 1060 " Cadherins 1063 Classic cadherins 1063 Protocadherins 1064 Integrins 1066 Selectins 1067 Syndecans 1067 Immunoglobulin superfamily 1067 1022 "$ Serine/threonine kinases 1069 AGC (PKA, PKG and PKC containing) group 1069 CAMK (Calcium-calmodulin dependent protein kinase) group 1071 CK1 (Casein kinase 1) group 1073 CMGC (CDK, MAPK, GSK3 and CLK containing) group 1073 RGC (Receptor guanylyl cyclase) group 1074 STE (Sterile-7, -11 and -20 homologous) group 1075 TKL (Tyrosine kinase-like) group 1076 Atypical group 1077 Other groups 1078 Tyrosine kinases 1080 RTK (Receptor tyrosine kinase) group 1080 NRTK (Non-receptor tyrosine kinase) group 1081 % Receptor proteins are specialized structures that are able to nases, receptor serine/threonine kinases or receptor recognize mostly diffusable molecules with a very high spe- guanylyl cyclases. cificity and that are able to reversibly bind them with a high Receptors without intrinsic effector function interact with affinity. Ligand binding to the receptor initiates a signal proteins that are either effectors themselves or that can reg- transduction process which propagates the message of the ulate effectors. The largest group of such receptors are the G- ligand. There are many different types of receptors that dif- protein coupled receptors (GPCRs). Via heterotrimeric G- fer especially in their mode of signal propagation. Most re- proteins they are able to regulate the activity of a variety of ceptors are cell-surface receptors and respond to ligands effector proteins (enzymes, ion channels). Other receptors that usually cannot enter the cell. Lipophilic molecules (e.g. such as the cytokine receptors interact with and activate cy- steroids), however, are able to enter the cell and can act on tosolic protein kinases (Jak-family) upon ligand binding. A intracellular receptors. third group of receptors (TNF-receptor superfamily, IL-1/Toll- The group of cell-surface receptors can be subdivid- like receptors) recruit adaptor proteins (e.g. TRADD, MyD88) ed into those with an intrinsic effector function (en- following ligand-dependent activation which then serve as a zymes, ion channels) and others without intrinsic platform for the formation of an effector complex consisting effector function. The first group consists of receptor of various other proteins. operated ion channels or receptors with intrinsic enzy- The majority of intracellular receptors are so-called “nu- matic activity. In both cases the intrinsic effector func- clear receptors”. They are transcription factors that reside in tion is regulated by ligand binding. Receptors linked to the cytoplasm or nucleus and upon ligand binding translo- an intrinsic enzymatic activity are receptor tyrosine ki- cate to the nucleus to become transcriptionally active. Ligand-operated ion channels generate electrical signals in units two of which bind the ligand. Each subunit has four response to specific chemical neurotransmitters and are transmembrane domains. Heteropentameric channels are specialized in mediating the fast chemical synaptic trans- formed by GABAA-, glycine- nicotinic acetylcholine and, mission. Depending on their ion selectivity, ligand-gated 5-HT3-receptors. In contrast, the cation-selective iono- ion channels are either excitatory (glutamate-, P2X-, nico- tropic glutamate receptors have four subunits. Each subu- tinic, 5-HT3-receptors) or inhibitory (GABAA-, glycine-re- nit is able to bind glutamate. P2X purinoceptors subunits, ceptors). Ligand-gated ion channels can be grouped in finally, have only two transmembrane segments. P2X re- three distinct families based on the architecture of the ceptors are made up of three or four subunits. (᭤ Nicotinic channel. Most known ligand-operated ion channels con- Receptor, ᭤ Ionotropic Glutamate Receptor, ᭤ GABAergic sist of five subunits. This pentamer contains different sub- System, ᭤ Glycine Receptor). Receptor-subunit Ion selectivity Endogenous Ligand Ionotropic glutamate receptors NMDA receptors (tetrameric) NR1 Na+/K+/(Ca2+)Glutamate, Glycine NR2A Na+/K+/(Ca2+)Glutamate, Glycine NR2B Na+/K+/(Ca2+)Glutamate, Glycine NR2C Na+/K+/(Ca2+)Glutamate, Glycine NR2D Na+/K+/(Ca2+)Glutamate, Glycine NR3 Na+/K+/(Ca2+)Glutamate, Glycine AMPA receptors (tetrameric) GluR1 (GluR-A) Na+/K+ Glutamate GluR2 (GluR-B) Na+/K+ Glutamate GluR3 (GluR-C) Na+/K+ Glutamate GluR4 (GluR-D) Na+/K+ Glutamate 1024 Receptor Proteins Receptor-subunit Ion selectivity Endogenous Ligand Kainate receptors (tetrameric) GluR5 Na+/K+ Glutamate GluR6 Na+/K+ Glutamate GluR7 Na+/K+ Glutamate KA1 Na+/K+ Glutamate KA2 Na+/K+ Glutamate Purinoceptors (P2X) (trimeric) + + 2+ P2X1 Na /K /(Ca )ATP + + 2+ P2X2 Na /K /(Ca )ATP + + 2+ P2X3 Na /K /(Ca )ATP + + 2+ P2X4 Na /K /(Ca )ATP + + 2+ P2X5 Na /K /(Ca )ATP + + 2+ P2X6 Na /K /(Ca )ATP + + 2+ P2X7 Na /K /(Ca )ATP Nicotinic acetylcholine receptors (nAChR) (pentameric) Ligand-binding α1Na+/K+ Acetylcholine α2Na+/K+ Acetylcholine α3Na+/K+ Acetylcholine α4Na+/K+ Acetylcholine α6Na+/K+ Acetylcholine α7Na+/K+ Acetylcholine α8Na+/K+ Acetylcholine α9Na+/K+ Acetylcholine α10 Na+/K+ Acetylcholine Non-ligand-binding β1Na+/K+ β2Na+/K+ β3Na+/K+ β4Na+/K+ γ Na+/K+ δ Na+/K+ ε Na+/K+ Ionotropic serotonin receptors (5-HT3) (pentameric) + + 5-HT3A Na /K Serotonin + + 5-HT3B Na /K Serotonin Receptor-subunit Ion selectivity Endogenous Ligand GABAA receptors (pentameric) Ligand-binding α1Cl¯γ-Aminobutyric acid, (Benzodiazepines) α2Cl¯γ-Aminobutyric acid, (Benzodiazepines) α3Cl¯γ-Aminobutyric acid, (Benzodiazepines) α4Cl¯γ-Aminobutyric acid α5Cl¯γ-Aminobutyric acid, (Benzodiazepines) α6Cl¯γ-Aminobutyric acid Receptor Proteins 1025 Receptor-subunit Ion selectivity Endogenous Ligand Non-ligand-binding β1Cl¯ β2Cl¯ β3Cl¯ γ1Cl¯ γ2Cl¯ γ3Cl¯ δ Cl¯ ε Cl¯ θ Cl¯ ρ1Cl¯ ρ2Cl¯ ρ3Cl¯ Glycine receptors (GlyR) (pentameric) Ligand-binding α1Cl¯Glycine α2Cl¯Glycine α3Cl¯Glycine α4Cl¯Glycine Non-ligand-binding β Cl¯ 1026 Receptor Proteins Receptor tyrosine kinases (RTKs) are a group of trans- toplasmic domains. Tyrosine autophosphorylation of membrane receptors with an intrinsic tyrosine kinase ac- RTKs induces recruitment and activation of various sign- tivity. RTKs possess an extracellular ligand binding aling molecules via the interaction of SH2 (src homology domain and an intracellular conserved tyrosine kinase do- 2) or PTB (phosphotyrosine binding) domains with tyro- main. Almost 60 genes encoding RTKs have been identi- sine autophosphorylation sites at the cytoplasmic region. fied in the mammalian genome (Robinson et al., 2000, Some RTK ligands (e.g. FGFs) require accessory molecules Oncogene 19, 5548-5557). With the exception of members of for receptor activation. While some RTKs homodimerize, α β the insulin-receptor family that form 2 2 heterodimers, heterodimerization is a common feature among different all known RTKs are monomers which dimerize upon lig- RTK subfamilies. (᭤ Growth Factors, ᭤ Neurotrophic and binding resulting in autophosphorylation of their cy- Factors, ᭤ Insulin Receptor). Receptor Endogenous ligand(s) ErbB receptor family ErbB1 (EGFR) Epidermal growth factor (EGF), Heparin-binding (HB)- EGF, Transforming growth factor α (TGFα), Amphiregulin (AR), Betacellulin (BTC), Epiregulin (EPR) ErbB2 (Neu, HER2) dimerization partner for ErbB1,3,4 , no ligand so far found ErbB3 (HER3) Neuregulin-1 (Heregulin), Neuregulin-2 ErbB4 (HER4) Neuregulin-1, -2, -3, -4; BTC, HB-EGF, EPR Insulin-receptor family InsR Insulin IGF-1R Insulin-like growth factor-1 (IGF-1), IGF-2 InsRR (IRR) ? Platelet-derived growth factor-receptor family PDGFR-α / PDGFR-α PDGF-CC, PDGF-AA, PDGF-AB, PDGF-BB PDGFR-β / PDGFR-β PDGF-BB, PDGF-DD PDGFR-α / PDGFR-β PDGF-AA, PDGF-AB CSF-1R Colony stimulating factor (CSF) Kit/SCFR Stem cell factor (SCF, Steel factor) Flk2/Flt3 Flt3 Ligand Vascular endothelial growth factor (VEGF) receptor family VEGF-R1 (Flt-1) Placenta growth factor (PlGF), VEGF-A, VEGF-B VEGF-R2 (Flk-1) VEGF-A, VEGF-C, VEGF-D VEGF-R3 (Flt-4) VEGF-C, VEGF-D Fibroblast growth factor (FGF) receptor family FGF-R-1 FGF-1, -2, -3, -4, -5, -6, -10 FGF-R-2 FGF-1, -2, -3, -4, -5, -6, -7, -8, -9, -10 FGF-R-3 FGF-1, -2, -4, -8, -9 FGF-R-4 FGF-1, -2, -4, -6, -8, -9 KLG/CCK receptor family CCK4/PTK7 ? Nerve growth factor (NGF) receptor family TrkA Nerve growth factor (NGF) TrkB Brain derived neurotrophic factor (BDNF), Neurotrophin 4 (NT4), Neurotrophin 5, (NT5) TrkC Neurotrophin 3 (NT3) Receptor Proteins 1027 Receptor Endogenous ligand(s) Hepatocyte growth factor (HGF) receptor family Met HGF (Scatter factor) Ron/Skt Macrophage-stimulating protein (MSP) Eph family receptors EphA1 Ephrin-A1
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