Abstract
Phospholipase C-related, but catalytically inactive protein (PRIP) was first identified as a novel inositol 1,4,5-triphosphate binding protein. The PRIP-1 subtype is expressed predominantly in the central nervous system and binds directly to the GABA type A receptor (GABAA-R) β-subunit and several other proteins involved in the trafficking of GABAA-Rs to the plasma membrane. We found that the PRIP-1 knockout mouse showed an epileptic phenotype, confirmed by electroencephalogram. These ictal seizures were completely suppressed by diazepam (DZP), but the interictal discharges could not be abolished. We studied the electrophysiological properties of GABAergic transmission in hippocampal CA1 pyramidal neurons, using a slice patch-clamp technique. There was no difference in the effect of up to 1 μM DZP on the amplitude and frequency of miniature inhibitory postsynaptic currents between PRIP-1 knockout neurons versus wild-type neurons. In contrast, the amplitude of the tonic GABA current in PRIP-1 knockout neurons was markedly reduced compared with that in wild-type neurons. Consequently, the effect of DZP on PRIP-1 knockout mice was reduced. Dysfunction of extrasynaptic GABAergic transmission probably is involved in the epileptic phenotype of PRIP-1 knockout mice.
Footnotes
This work was supported in part by a Grant for Priority Research designated by the President of Hirosaki University; Grants-in-Aid for Scientific Research (S) [Grant 16109006]; Grants-in-Aid for Scientific Research (A) [Grant 18209035]; Grants-in-Aid for Scientific Research (B) [Grants 18300137, 18390316]; Grants-in-Aid for Scientific Research (C) [Grants 17590856, 20591361]; and Grants-in-Aid for Exploratory Research [Grants 1659272, 18659455], all provided by the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
ABBREVIATIONS:
- PRIP
- phospholipase C-related, but catalytically inactive protein
- DZP
- diazepam
- GABAA-R
- GABA type A receptor
- GABARAP
- GABAA-R-associated protein
- KO
- knockout
- BZP
- benzodiazepine
- BMI
- bicuculline methiodide
- EEG
- electroencephalogram
- MES
- maximal electroshock
- ACSF
- artificial cerebrospinal fluid
- mIPSC
- miniature inhibitory postsynaptic current
- PCR
- polymerase chain reaction
- PBST
- 0.05% Tween 20 in phosphate-buffered saline
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- WT
- wild type
- CGP55845
- (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl)phosphinic acid hydrochloride.
- Received April 9, 2011.
- Accepted November 28, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|