TY - JOUR AU - Szabó, Zsolt AU - Héja, László AU - Szalay, Gergely AU - Kékesi, Orsolya Sára AU - Füredi, András AU - Szebényi, Kornélia AU - Dobolyi, Árpád AU - Orbán, Tamás I. AU - Kolacsek, Orsolya AU - Tompa, Tamás AU - Miskolczy, Zsombor AU - Biczók, László AU - Rózsa J., Balázs AU - Sarkadi, Balázs AU - Kardos, Julianna TI - Extensive astrocyte synchronization advances neuronal coupling in slow wave activity in vivo JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 7 PY - 2017 PG - 18 SN - 2045-2322 DO - 10.1038/s41598-017-06073-7 UR - https://m2.mtmt.hu/api/publication/3251043 ID - 3251043 AB - Slow wave activity (SWA) is a characteristic brain oscillation in sleep and quiet wakefulness. Although the cell types contributing to SWA genesis are not yet identified, the principal role of neurons in the emergence of this essential cognitive mechanism has not been questioned. To address the possibility of astrocytic involvement in SWA, we used a transgenic rat line expressing a calcium sensitive fluorescent protein in both astrocytes and interneurons and simultaneously imaged astrocytic and neuronal activity in vivo. Here we demonstrate, for the first time, that the astrocyte network display synchronized recurrent activity in vivo coupled to UP states measured by field recording and neuronal calcium imaging. Furthermore, we present evidence that extensive synchronization of the astrocytic network precedes the spatial build-up of neuronal synchronization. The earlier extensive recruitment of astrocytes in the synchronized activity is reinforced by the observation that neurons surrounded by active astrocytes are more likely to join SWA, suggesting causality. Further supporting this notion, we demonstrate that blockade of astrocytic gap junctional communication or inhibition of astrocytic Ca2+ transients reduces the ratio of both astrocytes and neurons involved in SWA. These in vivo findings conclusively suggest a causal role of the astrocytic syncytium in SWA generation. LA - English DB - MTMT ER - TY - JOUR AU - Ma, X AU - Lubin, H AU - Ioja, Enikő AU - Kékesi, Orsolya Sára AU - Simon, Ágnes AU - Apáti, Ágota AU - Orbán, Tamás I. AU - Héja, László AU - Kardos, Julianna AU - Marko, IE TI - Straightforward and effective synthesis of gamma-aminobutyric acid transporter subtype 2-selective acyl-substituted azaspiro[4.5]decanes JF - BIOORGANIC & MEDICINAL CHEMISTRY LETTERS J2 - BIOORG MED CHEM LETT VL - 26 PY - 2016 IS - 2 SP - 417 EP - 423 PG - 7 SN - 0960-894X DO - 10.1016/j.bmcl.2015.11.100 UR - https://m2.mtmt.hu/api/publication/2988827 ID - 2988827 AB - Supply of major metabolites such as gamma-aminobutyric acid (GABA), beta-alanine and taurine is an essential instrument that shapes signalling, proper cell functioning and survival in the brain and peripheral organs. This background motivates the synthesis of novel classes of compounds regulating their selective transport through various fluid-organ barriers via the low-affinity gamma-aminobutyric acid (GABA) transporter subtype 2 (GAT2). Natural and synthetic spirocyclic compounds or therapeutics with a range of structures and biological activity are increasingly recognised in this regard. Based on pre-validated GABA transport activity, straightforward and efficient synthesis method was developed to provide an azaspiro[4.5]decane scaffold, holding a variety of charge, substituent and 3D constrain of spirocyclic amine. Investigation of the azaspiro[4.5]decane scaffold in cell lines expressing the four GABA transporter subtypes led to the discovery of a subclass of a GAT2-selective compounds with acyl-substituted azaspiro[4.5]decane core. LA - English DB - MTMT ER - TY - JOUR AU - Kékesi, Orsolya Sára AU - Ioja, Enikő AU - Szabó, Zsolt AU - Kardos, Julianna AU - Héja, László TI - Recurrent seizure-like events are associated with coupled astroglial synchronization. JF - FRONTIERS IN CELLULAR NEUROSCIENCE J2 - FRONT CELL NEUROSCI VL - 9 PY - 2015 SN - 1662-5102 DO - 10.3389/fncel.2015.00215 UR - https://m2.mtmt.hu/api/publication/2972588 ID - 2972588 N1 - PMC PMC4471369 Funding Agency and Grant Number: ERA-Chemistry OTKAOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [102166]; NKFP NANOSEN9 [TECH-09-AI-2009-0117]; TRANSRAT [KMR_12-1-2012-0112] Funding text: This work was supported by grants ERA-Chemistry OTKA 102166, TECH-09-AI-2009-0117 NKFP NANOSEN9 and KMR_12-1-2012-0112 TRANSRAT. The authors thank Erzsebet Kutine Fekete for the excellent technical assistance. Cited By :20 Export Date: 6 April 2021 Correspondence Address: Héja, L.; Research Centre for Natural Sciences, Magyar tudósok körútja 2, Hungary Cited By :20 Export Date: 7 April 2021 Correspondence Address: Héja, L.; Research Centre for Natural Sciences, Magyar tudósok körútja 2, Hungary AB - Increasing evidence suggest that astrocytes significantly modulate neuronal function at the level of the tripartite synapse both in physiological and pathophysiological conditions. The global control of the astrocytic syncytium over neuronal networks, however, is still less recognized. Here we examined astrocytic signaling during epileptiform activity which is generally attributed to large-scale neuronal synchronization. We show that seizure-like events in the low-[Mg(2+)] in vitro epilepsy model initiate massive, long-range astrocytic synchronization which is spatiotemporally coupled to the synchronized neuronal activity reaching its maximum at the electrographic tonic/clonic transition. Cross-correlation analysis of neuronal and astrocytic Ca(2+) signaling demonstrates that high degree of synchronization arises not only among astrocytes, but also between neuronal and astrocyte populations, manifesting in astrocytic seizure-like events. We further show that astrocytic gap junction proteins contribute to astrocytic synchronization since their inhibition by carbenoxolone (CBX) or Cx43 antibody increased the interictal interval and in 41% of slices completely prevented recurrent seizure-like activity. In addition, CBX also induced unsynchronized Ca(2+) transients associated with decreasing incidence of epileptiform discharges afterwards. We propose therefore that local, unsynchronized astrocytic Ca(2+) transients inhibit, while long-range, synchronized Ca(2+) signaling contributes to the propagation of recurrent seizure-like events. LA - English DB - MTMT ER - TY - JOUR AU - Szabó, Mónika AU - Veres, Zsuzsa AU - Bátai-Konczos, Attila AU - Kékesi, Orsolya Sára AU - Kis, Emese AU - Szabó, K AU - Jemnitz, Katalin TI - Statins alter the hepatobiliary transport of unconjugated and conjugated bilirubin in sandwich-cultured rat hepatocytes. nincs TS - nincs JF - TOXICOLOGY IN VITRO J2 - TOXICOL IN VITRO VL - 28 PY - 2014 IS - 6 SP - 1136 EP - 1143 PG - 8 SN - 0887-2333 DO - 10.1016/j.tiv.2014.05.016 UR - https://m2.mtmt.hu/api/publication/2760570 ID - 2760570 LA - English DB - MTMT ER - TY - JOUR AU - Kékesi, Orsolya Sára AU - Nyitrai, Gabriella AU - Szabó, Pál Tamás AU - Fiáth, Richárd AU - Ulbert, István AU - Kardos, Julianna AU - Héja, László TI - GLIAL GABA TRANSPORTERS DOWNREGULATE ENHANCED NEURONAL ACTIVITY JF - GLIA J2 - GLIA VL - 61 PY - 2013 IS - 1 SP - S122 EP - S123 PG - 2 SN - 0894-1491 UR - https://m2.mtmt.hu/api/publication/2540335 ID - 2540335 N1 - 11th European Meeting on Glial Cell Function in Health and Disease JUL 03-06, 2013. Berlin, GERMANY SU 1 LA - English DB - MTMT ER - TY - JOUR AU - Muranyi, M AU - Cinar, Resat AU - Kékesi, Orsolya Sára AU - Birkás, Erika AU - Fábián, Gabriella AU - Bozó, Bea AU - Zentai, A AU - Tóth, Géza AU - Kicsi, EG AU - Macsai, M AU - Dochnal, Roberta AU - Szabó, Gyula AU - Szűcs, Mária TI - Ligand-Specific Regulation of the Endogenous Mu-Opioid Receptor by Chronic Treatment with Mu-Opioid Peptide Agonists JF - BIOMED RESEARCH INTERNATIONAL J2 - BIOMED RES INT VL - 2013 PY - 2013 PG - 9 SN - 2314-6133 DO - 10.1155/2013/501086 UR - https://m2.mtmt.hu/api/publication/2486869 ID - 2486869 AB - Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid(2)-endomorphin-2 (ACHC-EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu-agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the "so-called biased agonism" or "functional selectivity". LA - English DB - MTMT ER - TY - JOUR AU - Cinar, Resat AU - Kékesi, Orsolya Sára AU - Birkás, Erika AU - Fábián, Gabriella AU - Schmidhammer, H AU - Szűcs, Mária TI - Lack of Regulatory Changes of mu-Opioid Receptors by 14-Methoxymetopon Treatment in Rat Brain. Further Evidence for Functional Selectivity. JF - CURRENT PHARMACEUTICAL DESIGN J2 - CURR PHARM DESIGN VL - 19 PY - 2013 SP - 7348 EP - 7354 PG - 7 SN - 1381-6128 DO - 10.2174/138161281942140105161245 UR - https://m2.mtmt.hu/api/publication/2429176 ID - 2429176 AB - Here we have studied regulatory changes of mu-opioid receptors accompanying in vivo 14-methoxymetopon treatments of rats. Previously, this ligand has been shown to be an extremely potent, centrally acting mu-opioid specific analgesic with low physical dependence, tolerance, respiratory depression, constipation and other side effects. Our work shows that it is a highly potent full agonist of mu-opioid receptor coupled G-protein signaling in vitro, alike the well-known opioid agonist, etorphine. However, unlike etorphine, which desensitized and down-regulated the endogenous mu-opioid receptors, 14-methoxymetopon, given to rats intraperitoneally (i.p.) either acutely or chronically, did not change the binding or G-protein signaling of mu-opioid receptors in rat brain subcellular membranes. Thereby, these data provide further evidence that there is no direct relationship between the efficacy of the ligand in signaling and its ability to internalize or desensitize the receptor. Viewed collectively with published work, it is discussed that mu-opioid receptors display functional selectivity, also called 'biased agonism'. This concept implies that each ligand may induce unique, ligand-specific receptor conformation that can result in distinct agonist-directed trafficking and/or signal transduction pathways associated with the receptor. Ligand-specific signaling may open up new directions for designing potent analgesics that do not interact with unwanted signaling pathways, which mediate undesired side-effects, such as tolerance and dependence. LA - English DB - MTMT ER - TY - JOUR AU - Nyitrai, Gabriella AU - Kékesi, Orsolya Sára AU - Pál, Ildikó AU - Keglevich, Péter AU - Csíki, Zsuzsanna AU - Fügedi, Péter AU - Simon, Ágnes AU - Fitos, Ilona AU - Németh, Krisztina AU - Benéné Visy, Júlia AU - Tárkányi, Gábor AU - Kardos, Julianna TI - Assessing toxicity of polyamidoamine dendrimers by neuronal signaling functions JF - NANOTOXICOLOGY J2 - NANOTOXICOLOGY VL - 6 PY - 2012 IS - 6 SP - 576 EP - 586 PG - 11 SN - 1743-5390 DO - 10.3109/17435390.2011.591511 UR - https://m2.mtmt.hu/api/publication/2060849 ID - 2060849 N1 - Early Online: pp. 1-13. (2011) Funding Agency and Grant Number: Nanotransport [CRC-HAS_2009]; NANOSEN9 [TECH-09-A1-2009-0117]; [GVOP-3.2.1.-2004-04-0210/3.0] Funding text: We thank Nanotransport (CRC-HAS_2009), NANOSEN9 (TECH-09-A1-2009-0117) and GVOP-3.2.1.-2004-04-0210/3.0 projects for financial support. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. LA - English DB - MTMT ER - TY - JOUR AU - Héja, László AU - Nyitrai, Gabriella AU - Kékesi, Orsolya Sára AU - Dobolyi, Árpád AU - Szabó, Pál Tamás AU - Fiáth, Richárd AU - Ulbert, István AU - Pál-Szenthe, Borbála AU - Palkovits, Miklós AU - Kardos, Julianna TI - Astrocytes convert network excitation to tonic inhibition of neurons JF - BMC BIOLOGY J2 - BMC BIOL VL - 10 PY - 2012 PG - 21 SN - 1741-7007 DO - 10.1186/1741-7007-10-26 UR - https://m2.mtmt.hu/api/publication/1942337 ID - 1942337 N1 - Department of Functional Pharmacology, Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri 59-67, 1025 Budapest, Hungary Laboratory of Neuromorphology and Neuroendocrinology, Semmelweis University and Hungarian Academy of Sciences, Tuzoltó 58, 1094 Budapest, Hungary Department of Biochemical Pharmacology, Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri 59-67, 1025 Budapest, Hungary Comparative Psychophysiology Group, Institute of Cognitive Neuroscience and Psychology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Victor Hugo 18-22, 1132 Budapest, Hungary Péter Pázmány Catholic University, Faculty of Information Technology, Práter 50A, 1083 Budapest, Hungary Cited By :98 Export Date: 20 March 2021 Correspondence Address: Héja, L.; Department of Functional Pharmacology, Pusztaszeri 59-67, 1025 Budapest, Hungary; email: heja.laszlo@ttk.mta.hu Chemicals/CAS: 4 aminobutyric acid, 28805-76-7, 56-12-2; glutamate decarboxylase, 9024-58-2; glutamic acid, 11070-68-1, 138-15-8, 56-86-0, 6899-05-4; GABA Plasma Membrane Transport Proteins; Glutamate Decarboxylase, 4.1.1.15; Glutamate Plasma Membrane Transport Proteins; Glutamic Acid, 56-86-0; gamma-Aminobutyric Acid, 56-12-2 Department of Functional Pharmacology, Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri 59-67, 1025 Budapest, Hungary Laboratory of Neuromorphology and Neuroendocrinology, Semmelweis University and Hungarian Academy of Sciences, Tuzoltó 58, 1094 Budapest, Hungary Department of Biochemical Pharmacology, Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri 59-67, 1025 Budapest, Hungary Comparative Psychophysiology Group, Institute of Cognitive Neuroscience and Psychology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Victor Hugo 18-22, 1132 Budapest, Hungary Péter Pázmány Catholic University, Faculty of Information Technology, Práter 50A, 1083 Budapest, Hungary Cited By :99 Export Date: 31 March 2021 Correspondence Address: Héja, L.; Department of Functional Pharmacology, Pusztaszeri 59-67, 1025 Budapest, Hungary; email: heja.laszlo@ttk.mta.hu Chemicals/CAS: 4 aminobutyric acid, 28805-76-7, 56-12-2; glutamate decarboxylase, 9024-58-2; glutamic acid, 11070-68-1, 138-15-8, 56-86-0, 6899-05-4; GABA Plasma Membrane Transport Proteins; Glutamate Decarboxylase, 4.1.1.15; Glutamate Plasma Membrane Transport Proteins; Glutamic Acid, 56-86-0; gamma-Aminobutyric Acid, 56-12-2 Funding Agency and Grant Number: NKFP MediChem2 [1/A/005/2004]; ERA-Chemistry [OTKA 102166, OTKA K 81357]; TET NEUROGEN; TET MULTISCA; NKFP NANOSEN9 [TECH-09-AI-2009-0117]; CRC-HAS-2009-Nanotransport; [GVOP-3.2.1.-2004-04-0210/3.0 Transporter Explorer AKF-050068] Funding text: This work was supported by grants 1/A/005/2004 NKFP MediChem2, GVOP-3.2.1.-2004-04-0210/3.0 Transporter Explorer AKF-050068, ERA-Chemistry OTKA 102166, OTKA K 81357, TET NEUROGEN, TET MULTISCA to IU, TECH-09-AI-2009-0117 NKFP NANOSEN9 and CRC-HAS-2009-Nanotransport. Department of Functional Pharmacology, Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri 59-67, 1025 Budapest, Hungary Laboratory of Neuromorphology and Neuroendocrinology, Semmelweis University and Hungarian Academy of Sciences, Tuzoltó 58, 1094 Budapest, Hungary Department of Biochemical Pharmacology, Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri 59-67, 1025 Budapest, Hungary Comparative Psychophysiology Group, Institute of Cognitive Neuroscience and Psychology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Victor Hugo 18-22, 1132 Budapest, Hungary Péter Pázmány Catholic University, Faculty of Information Technology, Práter 50A, 1083 Budapest, Hungary Cited By :99 Export Date: 6 April 2021 Correspondence Address: Héja, L.; Department of Functional Pharmacology, Pusztaszeri 59-67, 1025 Budapest, Hungary; email: heja.laszlo@ttk.mta.hu LA - English DB - MTMT ER - TY - CHAP AU - Pál, Ildikó AU - Nyitrai, Gabriella AU - Kékesi, Orsolya Sára AU - Simon, Ágnes AU - Kardos, Julianna ED - Kiss, T ED - Perczel, A TI - Interactions of polyamidoamine dendrimers with the plasmamembrane of neuronal cells T2 - 4th European Conference on Chemistry for Life Sciences 4 ECCLS PB - Monduzzi International Proceedings Division CY - Bologna SN - 9788875876319 T3 - Monduzzi Editore International Proceedings Division PY - 2011 SP - 75 EP - 78 PG - 4 UR - https://m2.mtmt.hu/api/publication/1866287 ID - 1866287 LA - English DB - MTMT ER -