Activation and Inhibition of Neuronal G Protein-Gated Inwardly Rectifying K+ Channels by P2Y Nucleotide Receptors

• DOI: 10.1124/mol.66.3
• Publication Date: 2004-09-01
• Authors: Im, JY Im, Joo-Young; Kim, D Kim, Doyeun; Lee, KW Lee, Kang...; Kim, JB Kim, Jung...; Lee, JK Lee, Ja-K...; Kim, DS Kim, Dong...; Lee, YI Lee, Youn...; Ha, KS Ha, Kwon-Soo; Joe, CO Joe, Cheol O; Han, PL Han, Pyun...
• Keywords: Polychlorinated Dibenzodioxins; Histidine Kinase; Flavonols; Base Pair Mismatch; Biguanides; Receptors, Cytoplasmic and Nuclear; Cell Cycle Proteins; Apoptosis; Microtubules; Spinal Cord -- drug effects -- physiology; Receptors, Tumor Necrosis Factor; Rats, Sprague-Dawley; Receptors, Purinergic P2Y1; Mice; Xenopus laevis; Tumor Cells, Cultured; Topoisomerase II Inhibitors; Serotonin 5-HT3 Receptor Antagonists; Cyclic GMP; Lung; Cells, Cultured; Oligonucleotide Array Sequence Analysis; Serotonin Plasma Membrane Transport Proteins; Mice, Inbred ICR; Cultured; [CHIM.ORGA]Chemical Sciences/Organic chemistry; Sciences bio-médicales et agricoles; Endocytosis; Tumor Cells; I-kappa B Kinase; Zinc; Spinal Cord; 5-HT3 -- genetics -- metabolism -- physiology; Hepatocyte Nuclear Factor 1; Fibroblast Growth Factor 2; Cell Division; Amsacrine; G2 Phase; Serotonin; Tropisetron; Diacetyl; 03 medical and health sciences; 616; Cytochrome P-450 CYP1A1; Gene Silencing; Amino Acid Sequence; RNA, Messenger; Acetaminophen; Ions; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Tumor Necrosis Factor-alpha; Lysine; JNK Mitogen-Activated Protein Kinases; Proteins; Lidocaine; DNA; Fibronectins; Protein Structure, Tertiary; Checkpoint Kinase 2; Receptors, Aryl Hydrocarbon; beta-Adrenergic Receptor Kinases; Checkpoint Kinase 1; 570 Life sciences; biology; U.S. Gov't; Calcium Channels; Receptors, Serotonin, 5-HT3; Analgesics -- pharmacology; Reactive Oxygen Species; Transcription Factors; Models, Molecular; rho GTP-Binding Proteins; Time Factors; Protein Conformation; Receptors, Leukotriene B4; Organic Anion Transporters; Gene Expression; Antisense -- pharmacology; Organic Anion Transporters, Sodium-Independent; Drug Screening Assays; P.H.S.; Ion Channels; Body Temperature; Phosphatidylinositol 3-Kinases; Calcium Channels, N-Type; NF-KappaB Inhibitor alpha; Osteogenesis; Myocytes, Cardiac; Hepatocyte Nuclear Factor 1-alpha; Pyrophosphatases; Insulin-Like Growth Factor I; Apigenin; Biliary Tract; Luteolin; Zebrafish; Protein Kinase C; Mice, Knockout; Mice, Inbred C3H; Cell Death; Pregnane X Receptor; Imidazoles; Nuclear Proteins; Tyrphostins; Intercellular Adhesion Molecule-1; Mitochondria; Isoenzymes; Tranexamic Acid; Blood-Brain Barrier; /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; I-kappa B Proteins; Rabbits; Serotonin Antagonists; Somatostatin; Indazoles; Nerve Tissue Proteins; Mice, Transgenic; Protein Serine-Threonine Kinases; Tritium; Leukotriene B4; Xenobiotics; Dogs; GTP-Binding Proteins; Vesicular Biogenic Amine Transport Proteins; Animals; Protein Kinase Inhibitors; Diethylstilbestrol; Flavonoids; Aspartic Acid; Base Sequence; Aryl Hydrocarbon Receptor Nuclear Translocator; Biological Transport; Zebrafish Proteins; TNF Receptor-Associated Factor 1; Cyclic AMP-Dependent Protein Kinases; Rats; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Gene Expression Regulation; Cyclooxygenase 2; Guanosine 5'-O-(3-Thiotriphosphate); Mutagenesis, Site-Directed; Oocytes; RNA; Calcium; Camptothecin; Drug Screening Assays, Antitumor; Copper; Interleukin-1; Phosphatidylinositol 4,5-Diphosphate; Cell Extracts; Male; Integrins; Embryo, Nonmammalian; DNA Repair; Ataxia Telangiectasia Mutated Proteins; Sodium Channels; Enzyme Inhibitors; Oxazoles; Etoposide; Cerebral Cortex; Neurons; 0303 health sciences; Arachidonic Acid; Membrane Glycoproteins; 10061 Institute of Molecular Cancer Research; Cell Cycle; NF-kappa B; 3T3 Cells; Immunohistochemistry; Serotonin Antagonists -- pharmacology; Up-Regulation; Fetal Diseases; Teratogens; DNA Topoisomerases, Type I; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; COS Cells; Liver Extracts; Anions; Blood Platelets; Transcriptional Activation; Dynamins; Paclitaxel; Metabolic Clearance Rate; Blotting, Western; Molecular Sequence Data; SUMO-1 Protein; Down-Regulation; Antineoplastic Agents; Polyenes; Small Interfering; EAAT ; excitatory amino acid transporter ; HIP-A; Transfection; Dinoprostone; Structure-Activity Relationship; SDG 3 - Good Health and Well-being; Cations; Potassium Channel Blockers; Humans; Cyclooxygenase Inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1; Potassium Channels, Inwardly Rectifying; Kaempferols; Antineoplastic Agents, Alkylating; Osteoblasts; Tibia; Receptors, Purinergic P2; Myocardium; Neuropeptides; Calcium-Binding Proteins; G1 Phase; MPTP Poisoning; Membrane Transport Proteins; Epithelial Cells; Oligonucleotides, Antisense; Clathrin; Cytoskeletal Proteins; Acetaminophen -- pharmacology; Mutation; Endothelium, Vascular; Topoisomerase I Inhibitors; Deoxyuracil Nucleotides; Carrier Proteins; Protein Kinases; Lipopolysaccharides; Indoles -- pharmacology; Receptors, Steroid; Radiation-Sensitizing Agents; Potassium Channels; Indoles; Arrestins; Carboxylic Acids; Oligodeoxyribonucleotides, Antisense; Neuroblastoma; Hypothermia, Induced; GTP-Binding Protein gamma Subunits; Cricetinae; Receptors; Enzyme Stability; Serine; Drug Interactions; Phosphorylation; RNA, Small Interfering; Promoter Regions, Genetic; Analgesics; GTP-Binding Protein beta Subunits; Calcium Channel Blockers; Drug Resistance, Multiple; Multidrug Resistance-Associated Protein 2; Dacarbazine; DNA-Binding Proteins; Electrophysiology; 3004 Pharmacology; Oligodeoxyribonucleotides; Female; Multidrug Resistance-Associated Proteins; Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-fos; Signal Transduction; Sodium Channel Blockers; Myocytes, Smooth Muscle; Carbazoles; Mitosis; TRPM Cation Channels; Glutamic Acid; Breast Neoplasms; CHO Cells; Myosins; Research Support; Vinblastine; Cell Line; Solute Carrier Organic Anion Transporter Family Member 1B3; Potassium Channels, Tandem Pore Domain; Journal Article; Temozolomide; Cyclic GMP-Dependent Protein Kinases; Biguanides -- pharmacology; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Hepatocyte Nuclear Factor 1-beta; Binding Sites; Sequence Homology, Amino Acid; Ubiquitin; Membrane Proteins; Antitumor; Thymidylate Synthase; [CHIM.ORGA] Chemical Sciences/Organic chemistry; Transcription Factor AP-1; Oxidative Stress; Kinetics; DNA Topoisomerases, Type II; Amino Acid Substitution; Prostaglandin-Endoperoxide Synthases; 1313 Molecular Medicine; Type C Phospholipases; Vesicular Monoamine Transport Proteins; Phenytoin; Tumor Suppressor Protein p53; DNA Damage; Synaptosomes

Intercellular adhesion molecule-1 (ICAM-1) has been implicated in the processes of inflammation and carcinogenesis. Flavonoids, which are polyphenolic compounds with a wide distribution throughout the plant kingdom, have potent anti-inflammatory properties. We investigated the effects of flavonols (kaempferol, quercetin, and myricetin) and flavones (flavone, chrysin, apigenin, luteolin, baicalein, and baicalin) on the tumor necrosis factor-alpha (TNF-alpha)-stimulated ICAM-1 expression. Among those flavonoids tested, kaempferol, chrysin, apigenin, and luteolin are active inhibitors of ICAM-1 expression. Additional experiments suggested that apigenin and luteolin were actively inhibiting the IkappaB kinase (IKK) activity, the IkappaBalpha degradation, the nuclear factor-kappaB (NF-kappaB) DNA-protein binding, and the NF-kappaB luciferase activity. TNF-alpha-induced ICAM-1 promoter activity was attenuated using an activator protein-1 (AP-1) site deletion mutant, indicating the involvement of AP-1 in ICAM-1 expression. AP-1-specific DNA-protein binding activity was increased by TNF-alpha, and the supershift assay identified the components of c-fos and c-jun. Extracellular signal-regulated kinase (ERK) and p38 were involved in the c-fos mRNA expression, and c-Jun NH(2)-terminal kinase (JNK) was involved in the c-jun mRNA expression. All three mitogen-activated protein kinase (MAPK) activities were inhibited by apigenin and luteolin. In comparison, kaempferol and chrysin only inhibited the JNK activity. The inhibitory effects of apigenin and luteolin on ICAM-1 expression are mediated by the sequential attenuation of the three MAPKs activities, the c-fos and c-jun mRNA expressions, and the AP-1 transcriptional activity. IKK/NF-kappaB pathway is also involved; however, kaempferol- and chrysin-mediated inhibitions are primarily executed through the attenuation of JNK activity, c-jun mRNA expression, and AP-1 activity. The structure-activity relationships are also explored, and the important role of -OH group at positions 5 and 7 of A ring and at position 4 of B ring is noted. Finally, our results suggested that AP-1 seems to play a more significant role than NF-kappaB in the flavonoid-induced ICAM-1 inhibition.