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13Th Symposium of the Austrian Pharmacological Society (APHAR) APHAR 2007 Abstract Preview for publication in BMC Pharmacology Meeting abstracts 13th Symposium of the Austrian Pharmacological Society (APHAR) Joint meeting with the Austrian Society of Toxicology (ASTOX) and the Hungarian Society for Experimental and Clinical Pharmacology (MFT) Vienna, Austria 22–24 November 2007 AUSTRIAN PHARMACOLOGICAL SOCIETY A2 A1 Restricted expression between parvalbumin and Neurokinin 1 receptor antagonism promotes active substance P receptor NK1 in interneurones of the stress coping via enhanced septal 5-HT lateral amygdala transmission Hari Kishore Sreepathi and Francesco Ferraguti Georg M Singewald1, Karl Ebner1, Nigel Whittle1, Department of Pharmacology, Medical University of Francesco Ferraguti2 and Nicolas Singewald2 Innsbruck, Austria 1Department of Pharmacology and Toxicology, Center E-Mail: [email protected] for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria Increasing evidence suggests that substance P (SP) and its receptor, namely the neurokinin 1 receptor (NK -R), play an 2Department of Pharmacology, Medical University of 1 important role in the modulation of stress-related, affective Innsbruck, Austria and/or anxious behaviours. Both SP and NK1-R are E-Mail: [email protected] expressed in brain regions critically involved in stress, fear and affective responses such as the amygdala, Antagonists of the substance P (SP) preferring neurokinin 1 hippocampus and frontal cortex. In this study we aimed at receptor (NK1-R) represent a promising novel class of drugs identifying the types of NK -R immunoreactive neurones in for the treatment of stress-related disorders including 1 the basolateral complex of the amygdala according to their depression and anxiety disorders. The underlying neuronal content of other neurochemical markers by dual or triple mechanisms involved in the effects of these drugs, however, labelling immunofluorescence. The basolateral amygdaloid are poorly understood. By using in vivo microdialysis we complex consists of the lateral (LA) and basolateral (BL) observed increased SP, but reduced serotonin (5-HT) nuclei, which are believed to be cytoarchitectonically similar. release during forced swim stress (FST) in the rat lateral Our study reveals that in the rat LA, 38.7 ± 6.7% of NK -R septum (LS), a key area in processing emotions and stress 1 immunopositive interneurones (124 ⁄ 331) co-express the responses. Acute administration of the selective high affinity calcium binding protein parvalbumin (PV), representing 15.2 NK1-R antagonist L-822429 injected either systemically or ± 3.4% (124 ⁄ 820) of PV+ neurones. Conversely, in the BL locally into the LS reversed the FST-induced decrease in no coexistence between NK -R (293 neurones counted) and 5-HT efflux and facilitated active coping strategies during the 1 parvalbumin (2385 neurones counted) expressing FST. Increased active coping in the FST was attenuated by interneurones was detected. These results suggest that intraseptal 5-HT1A-R blockade with WAY100635, indicating interneurones in the LA and BL differentially express that the behavioural effect during NK1-R blockade is molecules involved in cell signalling and indicate a distinct mediated by enhanced intraseptal serotonergic transmission organization in local interneurones. The BL resemble the acting on 5-HT1A-R. Taken together, our findings identify the hippocampal region CA1, in which NK -R-expressing LS as an important brain area for the modulation of stress 1 neurones do not coexist with PV [1]. responses by the SP/NK1-R system. NK1-R blockade References resulted in behaviorally significant enhancement of 5-HT 1. Acsády L, Katona I, Gulyás AI, Shigemoto R and transmission. We show for the first time that this modulation Freund TF. Immunostaining for substance P receptor does not necessarily involve interaction with neuronal firing labels GABAergic cells with distinct termination at the cell body level of 5-HT neurons as previously patterns in the hippocampus. J Comp Neurol 1997, postulated, but can be elicited in a terminal region of these 378:320–336. neurons. APHAR 2007 Abstract Preview for publication in BMC Pharmacology A3 A5 GPR55 is a novel cannabinoid receptor SAP102, a novel interaction partner of the A2A Nariman Balenga1, Andrew J Irving2 and adenosine receptor Maria Waldhoer1 Ingrid Gsandtner, Nicole Ferstl, Michael Freissmuth 1Department of Experimental and Clinical and Jürgen Zezula Pharmacology, Medical University of Graz, Austria Department of Pharmacology, Medical University of 2Neurosciences Institute, Division of Pathology and Vienna, Austria Neuroscience, University of Dundee, UK E-Mail: [email protected] E-Mail: [email protected] Adenosine receptors are G protein-coupled receptors and Cannabinoids exert their effects by binding to G protein- are implicated in several neurological and psychiatric coupled receptors (GPCRs). To date, two cannabinoid disorders such as Parkinson’s disease, schizophrenia and receptors have been cloned. The cannabinoid CB1 receptor Alzheimer’s disease. These receptors can be distinguished is one of the most abundant GPCRs in the central nervous by their affinity for adenosine analogues and by their system and plays an important role in pain transmission, preferred signal transduction pathway. The A2A receptor has feeding and the rewarding effects of cannabis, whereas the an unusually long intracellular carboxyl terminus. We CB2 receptor is predominantly found in immune cells. identified SAP102 (synapse-associated protein of 102 kDa) However, some effects of cannabinoids (especially in the as a novel interaction partner of the adenosine A2A receptor. vascular system) could not be attributed to either CB1 or CB2 SAP102 belongs to the family of MAGUK (membrane- receptor function. Here we present GPR55 as a putative associated guanylate kinase-like domain) proteins. These novel cannabinoid receptor, since GPR55 signals, binds to proteins have an established function in synaptic and internalizes in the presence of synthetic cannabinoid organization, which is reflected by their modular structure. ligands. Our data demonstrate that the A2A receptor binds to C-terminal domains of SAP102. Furthermore we identified A4 the responsible binding motif consisting of 5 amino acids in The hCMV chemokine receptor US28 prevents the receptor’s C-terminus. In hippocampal neurons we melanoma growth observed a co-localization of both proteins especialy in Elisabeth Moser1, Joshi Shripad2, Ping Quan2, punctuate structures along the neurite extensions that presumably represented dendritic spines. In the next step Helmut Seidl1,2, Sasa Frank3, Zhao-Jun Liu4, we will use several fluorescence-based techniques in order Mizuho Fukunaga4, Ronan McDaid4, Helmut Kerl2, 4 2 to investigate the influence of SAP102 on the mobility and Meenhard Herlyn , Helmut Schaider and targeting of the A receptor. 1 2A Maria Waldhoer 1 Departments of Experimental and Clinical A6 2 Pharmacology, Dermatology, and of Heterologous expression of membrane proteins in 3 MedicalBiochemistry and Microbiology, Medical cardiac myocytes University of Graz, Austria Miroslav Radenkovic, Halyna Pankevych, 4 The Wistar Institute, Philadelphia, PA, USA Oliver Kudlacek, Ingrid Gsandtner and E-Mail: [email protected] Karlheinz Hilber Department of Pharmacology, Center of Biomolecular The human cytomegalovirus (hCMV) encodes the G protein- coupled receptor (vGPCR) US28. This receptor signals Medicine and Pharmacology, Medical University of constitutively and interacts with a broad range of Vienna, Austria chemokines, which are crucial to the pathophysiological E-Mail: [email protected] significance and immunregulatory aspects of this receptor. The cardiac isoform of the Na+ channel (Na 1.5) is known to Chemokines and their receptors have been shown to be key V accumulate in the endoplasmic reticulum (ER). This determinants of tumor growth and formation of metastases. retention presumably reflects quality control in the ER. In US28 (and mutants thereof, i.e. US28R129A and order to understand the underlying mechanism, we US28Δ317) exert anti-tumorigenic effects in various heterologously expressed the human orthologue of the Na+ melanoma cell lines by scavenging chemokines from the channel (Na 1.5) in neonatal primary rat and murine tumor environment. Here we show that in contrast to all V cardiomyocytes, in a cardiomyoblast cell line (H9c2) and in other previously studied cell lines, US28 is expressed on the HEK293 cells (internal control). In HEK293 cells, Na 1.5 cell surface in the melanoma cell lines Sbcl2 and 451Lu. We V readily accumulated at the cell surface and gave rise to suggest that GASP – the G protein-coupled receptor- functional channels with the expected electrophysiological associated sorting protein – which sorts US28 and many properties. In contrast, in cardiomyocytes and H9c2 cells, other GPCRs to the lysosomes is absent in melanoma cells. the Na 1.5 accumulated in the ER regardless of the The absence of GASP might effect the tumor suppressing V transfection method employed (lipofection, nucleofection). properties of US28. As a positive control, we employed G protein-coupled β1-adrenergic, A1 and A2A adenosine receptors. In HEK293 cells, export of the A2A receptor is known to be enhanced by APHAR 2007 Abstract Preview for publication in BMC Pharmacology the deubiquinating enzyme USP4. Accordingly, we also co- A8 expressed USP4 and the A2A receptor in the different
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