title: Enhanced desensitization followed by unusual resensitization in GABAA receptors in phospholipase C-related catalytically inactive protein-1/2 double-knockout mice.
abstract: Phospholipase C-related catalytically inactive proteins (PRIP-1/2) are previously reported to be involved in the membrane trafficking of GABAA receptor (GABAAR) and the regulation of intracellular Ca(2+) stores. GABAAR-mediated currents can be regulated by the intracellular Ca(2+). However, in PRIP-1/2 double-knockout (PRIP-DKO) mice, it remains unclear whether the kinetic properties of GABAARs are modulated by the altered regulation of intracellular Ca(2+) 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 PRIP-DKO mice. The deletion of PRIP-1/2 enhanced the desensitization of IGABA but induced a hump-like tail current (tail-I) at the GABA puff offset. IGABA and the hump-like tail-I were suppressed by GABAAR antagonists. The enhanced desensitization of IGABA and the hump-like tail-I in PRIP-DKO PCs were mediated by increases in the intracellular Ca(2+) concentration and were largely abolished by a calcineurin inhibitor and ruthenium red. Calcium imaging revealed that Ca(2+)-induced Ca(2+) release (CICR) and subsequent store-operated Ca(2+) entry (SOCE) are more potent in PRIP-DKO PCs than in wild-type PCs. A mathematical model revealed that a slowdown of GABA-unbinding rate and an acceleration of fast desensitization rate by enhancing its GABA concentration dependency are involved in the generation of hump-like tail-Is. These results suggest that in L3 PCs of the barrel cortex in PRIP-DKO mice, the increased calcineurin activity due to the potentiated CICR and SOCE enhances the desensitization of GABAARs and slows the GABA-unbinding rate, resulting in their unusual resensitization following removal of GABA.
authors.affiliation: Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Toyoda
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.forename: Hajime
authors.initials: H
authors.lastname: Sato
authors.forename: Takuma
authors.initials: T
authors.lastname: Tanaka
authors.forename: Takeo
authors.initials: T
authors.lastname: Ogawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yatani
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kawano
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanematsu
authors.forename: Masato
authors.initials: M
authors.lastname: Hirata
authors.forename: Youngnam
authors.initials: Y
authors.lastname: Kang
mesh_terms: D000200:Action Potentials; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling; D020134:Catalytic Domain / Q000235:genetics; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D058787:GABA-A Receptor Antagonists; D047908:Intracellular Signaling Peptides and Proteins; C496391:Plcl1 protein, mouse; C530633:Plcl2 protein, mouse; D011963:Receptors, GABA-A
references.citation: J Physiol. 1987 Apr;385:243-86
references.pmid: 2443667
references.citation: PLoS One. 2011 Apr 26;6(4):e19285
references.pmid: 21541286
references.citation: Neuroreport. 1994 Oct 27;5(16):2073-6
references.pmid: 7865748
references.citation: J Neurochem. 2010 Jul;114(1):302-10
references.pmid: 20412381
references.citation: J Physiol. 1985 Mar;360:367-86
references.pmid: 2580971
references.citation: Life Sci. 2002 Dec 20;72(4-5):443-53
references.pmid: 12467885
references.citation: J Cell Physiol. 2005 Feb;202(2):422-33
references.pmid: 15468068
references.citation: J Neurosci. 1998 Nov 1;18(21):8590-604
references.pmid: 9786967
references.citation: Neuroreport. 1996 May 31;7(8):1421-6
references.pmid: 8856690
references.citation: J Biol Chem. 1992 Apr 5;267(10):6518-25
references.pmid: 1313009
references.citation: Neuron. 1991 Jul;7(1):17-25
references.pmid: 1648939
references.citation: J Neurochem. 1992 May;58(5):1643-51
references.pmid: 1313851
references.citation: J Neurosci. 1997 Oct 15;17(20):7626-33
references.pmid: 9315884
references.citation: Mol Pharmacol. 2009 Jun;75(6):1262-79
references.pmid: 19297520
references.citation: Ion Channels. 1992;3:83-136
references.pmid: 1384761
references.citation: Mol Cell Biol. 2003 Oct;23(20):7329-38
references.pmid: 14517301
references.citation: J Neurophysiol. 1998 Mar;79(3):1321-8
references.pmid: 9497413
references.citation: Neurosci Lett. 1996 Sep 6;215(2):95-8
references.pmid: 8888004
references.citation: J Physiol. 1987 Dec;394:85-98
references.pmid: 3502144
references.citation: Nature. 1986 Nov 13-19;324(6093):156-8
references.pmid: 2431316
references.citation: J Physiol. 1995 Jan 15;482 ( Pt 2):353-62
references.pmid: 7714826
references.citation: J Physiol. 1991 Jun;437:109-32
references.pmid: 1653849
references.citation: Proc Natl Acad Sci U S A. 1987 Feb;84(4):1118-22
references.pmid: 3029762
references.citation: Biochemistry. 2005 Jun 14;44(23):8523-32
references.pmid: 15938643
references.citation: Pflugers Arch. 2010 Jul;460(2):417-35
references.pmid: 20111871
references.citation: Neuron. 1995 Jul;15(1):181-91
references.pmid: 7542462
references.citation: Neurochem Res. 2013 Jun;38(6):1260-5
references.pmid: 23519933
references.citation: J Physiol. 1992 Feb;447:191-213
references.pmid: 1317428
references.citation: J Neurosci. 2002 Sep 15;22(18):7982-90
references.pmid: 12223551
references.citation: J Physiol. 2009 May 15;587(Pt 10):2115-25
references.pmid: 19332484
references.citation: Neuroscience. 1992;46(2):251-73
references.pmid: 1311812
references.citation: J Neurophysiol. 1995 May;73(5):2099-106
references.pmid: 7623101
references.citation: J Neurosci. 1994 Dec;14(12):7747-60
references.pmid: 7996209
references.citation: Neurosci Res. 1988 Jun;5(5):380-94
references.pmid: 2456501
references.citation: Biochem J. 1996 Jan 1;313 ( Pt 1):319-25
references.pmid: 8546702
references.citation: Biophys J. 1997 Dec;73(6):3349-57
references.pmid: 9414245
references.citation: J Pharmacol Exp Ther. 1998 Jul;286(1):243-55
references.pmid: 9655866
references.citation: J Pharmacol Exp Ther. 1999 Jun;289(3):1447-53
references.pmid: 10336538
references.citation: J Physiol. 1992 Oct;456:667-80
references.pmid: 1338107
references.citation: EMBO J. 2002 Mar 1;21(5):1004-11
references.pmid: 11867528
references.citation: J Neurosci. 2008 Jul 23;28(30):7574-84
references.pmid: 18650335
references.citation: J Neurosci. 2007 Feb 14;27(7):1692-701
references.pmid: 17301177
references.citation: Eur J Neurosci. 2003 Jun;17(11):2237-48
references.pmid: 12814357