KA-receptors (KARs) are widely expressed in the central nervous system and play an important role in short and long term plasticity (Andrade-Talavera et al., 2012). Because KARs are involved in presynaptic modulation of neurotransmitter release (Sihra and Moreno, 2013) and control both GABA and glutamate release (Jane et al., 2009) they represent a potential target for cognition and memory enhancement drugs. Compounds such as cyclothiazide and diazoxide, acting on AMPARs, potentiate glutamate currents through a removal of receptors desensitization (Yamada and Tang, 2003). More recently benzothiazides derivatives, such as 7-chloro-3- methyl-3, 4- dihydro - 2H-1,2,4-benzothiadiazine 1,1-dioxide (IDRA21) and 8-chloro-2,3,5,6- tetrahydro - 3,6-dimethyl-pyrrolo[1,2,3-de]-1,2,4-benzothiadiazine 1,1-dioxide (FUR) were studied because of their ability to cross more efficiently the blood brain barrier and their capability to potentiate AMPA receptor activity (Bertolino et al.1993; Battisti et al 2012). The modulation of these compounds of KAR activity was not investigated so far. By using the patch clamp technique in the whole cell configuration we studied IDRA21 and FUR on primary culture of cerebellum granule cells and in HEK293 transiently transfected with different subunits of KARs. KA-evoked currents were potentiated by both IDRA 21 and FUR, even though the latter compound was more potent (EC50IDRA21 191±58 μΜ; EC50RAC 7±2 μM). Co-application of KA and GYKI 53655, an antagonist of AMPAR, elicits a fast desensitizing current of low amplitude that was augmented in a dose-dependent manner by IDRA21 (EC50 = 538±240μM) and FUR (EC50 20±4μM). To investigate whether a selectivity of the effect for certain KARs subunit exists, we analyzed the effect of both IDRA21 and FUR in HEK293 cells transiently transfected with GluR5, GluR6 and GluR5-KA1 subunits. IDRA21 potentiates Glutamate-evoked currents in a dose-dependent fashion with EC50 of 595±167μM, 653±273μM and 668±271 in GluR5, GluR6 and GluR5-KA1, respectively. The potency of RAC was different in the diverse subunit assembly being higher in GluR5 expressing cells ( EC50=113±50μM, 188±95μM and 550±145μM for GluR5, GluR6 and GluR5-KA1, respectively). The efficacy of RAC was always higher than that of IDRA21 in all the subunit combination OASIS Helpdesk Powered by OASIS, The Online Abstract Submission and Invitation System SM © 1996 - 2014 Coe-Truman Technologies, Inc. All rights reserved. tested. Our data evidentiate that IDRA21 and FUR not only modulate AMPAR but also KAR activity. Considered the importance of KA receptors in memory procesess we think that these drugs exert their pharmacological effect also because of their capability of modulate this receptor activity. :
A Novel class of positive allosteric modulators of KA receptors / Puja, Giulia. - 476:(2014). (Intervento presentato al convegno Society for Neuroscience 44th Annual Meeting 2014 tenutosi a Washington D.C. nel 15-19 novembre).
A Novel class of positive allosteric modulators of KA receptors
PUJA, Giulia
2014
Abstract
KA-receptors (KARs) are widely expressed in the central nervous system and play an important role in short and long term plasticity (Andrade-Talavera et al., 2012). Because KARs are involved in presynaptic modulation of neurotransmitter release (Sihra and Moreno, 2013) and control both GABA and glutamate release (Jane et al., 2009) they represent a potential target for cognition and memory enhancement drugs. Compounds such as cyclothiazide and diazoxide, acting on AMPARs, potentiate glutamate currents through a removal of receptors desensitization (Yamada and Tang, 2003). More recently benzothiazides derivatives, such as 7-chloro-3- methyl-3, 4- dihydro - 2H-1,2,4-benzothiadiazine 1,1-dioxide (IDRA21) and 8-chloro-2,3,5,6- tetrahydro - 3,6-dimethyl-pyrrolo[1,2,3-de]-1,2,4-benzothiadiazine 1,1-dioxide (FUR) were studied because of their ability to cross more efficiently the blood brain barrier and their capability to potentiate AMPA receptor activity (Bertolino et al.1993; Battisti et al 2012). The modulation of these compounds of KAR activity was not investigated so far. By using the patch clamp technique in the whole cell configuration we studied IDRA21 and FUR on primary culture of cerebellum granule cells and in HEK293 transiently transfected with different subunits of KARs. KA-evoked currents were potentiated by both IDRA 21 and FUR, even though the latter compound was more potent (EC50IDRA21 191±58 μΜ; EC50RAC 7±2 μM). Co-application of KA and GYKI 53655, an antagonist of AMPAR, elicits a fast desensitizing current of low amplitude that was augmented in a dose-dependent manner by IDRA21 (EC50 = 538±240μM) and FUR (EC50 20±4μM). To investigate whether a selectivity of the effect for certain KARs subunit exists, we analyzed the effect of both IDRA21 and FUR in HEK293 cells transiently transfected with GluR5, GluR6 and GluR5-KA1 subunits. IDRA21 potentiates Glutamate-evoked currents in a dose-dependent fashion with EC50 of 595±167μM, 653±273μM and 668±271 in GluR5, GluR6 and GluR5-KA1, respectively. The potency of RAC was different in the diverse subunit assembly being higher in GluR5 expressing cells ( EC50=113±50μM, 188±95μM and 550±145μM for GluR5, GluR6 and GluR5-KA1, respectively). The efficacy of RAC was always higher than that of IDRA21 in all the subunit combination OASIS Helpdesk Powered by OASIS, The Online Abstract Submission and Invitation System SM © 1996 - 2014 Coe-Truman Technologies, Inc. All rights reserved. tested. Our data evidentiate that IDRA21 and FUR not only modulate AMPAR but also KAR activity. Considered the importance of KA receptors in memory procesess we think that these drugs exert their pharmacological effect also because of their capability of modulate this receptor activity. :
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