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Title of Journal: Pflugers Arch Eur J Physiol

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Abbravation: Pflügers Archiv - European Journal of Physiology

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Springer Berlin Heidelberg

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1432-2013

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Enhanced desensitization followed by unusual resen

Authors: Hiroki Toyoda Mitsuru Saito Hajime Sato Takuma Tanaka Takeo Ogawa Hirofumi Yatani Tsutomu Kawano Takashi Kanematsu Masato Hirata Youngnam Kang
Publish Date: 2014/04/16
Volume: 467, Issue: 2, Pages: 267-284
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Abstract

Phospholipase Crelated catalytically inactive proteins PRIP1/2 are previously reported to be involved in the membrane trafficking of GABAA receptor GABAAR and the regulation of intracellular Ca2+ stores GABAARmediated currents can be regulated by the intracellular Ca2+ However in PRIP1/2 doubleknockout PRIPDKO mice it remains unclear whether the kinetic properties of GABAARs are modulated by the altered regulation of intracellular Ca2+ stores Here we investigated whether GABAAR currents IGABA evoked by GABA puff in layer 3 L3 pyramidal cells PCs of the barrel cortex are altered in PRIPDKO mice The deletion of PRIP1/2 enhanced the desensitization of IGABA but induced a humplike tail current tailI at the GABA puff offset IGABA and the humplike tailI were suppressed by GABAAR antagonists The enhanced desensitization of IGABA and the humplike tailI in PRIPDKO PCs were mediated by increases in the intracellular Ca2+ concentration and were largely abolished by a calcineurin inhibitor and ruthenium red Calcium imaging revealed that Ca2+induced Ca2+ release CICR and subsequent storeoperated Ca2+ entry SOCE are more potent in PRIPDKO PCs than in wildtype PCs A mathematical model revealed that a slowdown of GABAunbinding rate and an acceleration of fast desensitization rate by enhancing its GABA concentration dependency are involved in the generation of humplike tailIs These results suggest that in L3 PCs of the barrel cortex in PRIPDKO mice the increased calcineurin activity due to the potentiated CICR and SOCE enhances the desensitization of GABAARs and slows the GABAunbinding rate resulting in their unusual resensitization following removal of GABAThe authors thank Dr N Akaike for critically reviewing an earlier version of the manuscript This study was supported by a GrantinAid for Scientific Research to YK B 22300127 and that to MH S 24229009 from Japan Ministry of Education Culture Sports Science and Technology


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