Enhanced desensitization followed by unusual resensitization in GABAA receptors in phospholipase C-related catalytically inactive protein-1/2 double-knockout mice

Hiroki Toyoda, Mitsuru Saito, Hajime Sato, Takuma Tanaka, Takeo Ogawa, Hirofumi Yatani, Tsutomu Kawano, Takashi Kanematsu, Masato Hirata, Youngnam Kang

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 Ca2+ stores. GABAAR-mediated currents can be regulated by the intracellular Ca2+. 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 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 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 Ca2+ concentration and were largely abolished by a calcineurin inhibitor and ruthenium red. Calcium imaging revealed that Ca2+-induced Ca2+ release (CICR) and subsequent store-operated Ca2+ 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.

Original languageEnglish
Pages (from-to)267-284
Number of pages18
JournalPflugers Archiv European Journal of Physiology
Volume467
Issue number2
DOIs
Publication statusPublished - Jan 1 2014

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Type C Phospholipases
GABA-A Receptors
Knockout Mice
Pyramidal Cells
gamma-Aminobutyric Acid
Tail
Proteins
GABA-A Receptor Antagonists
Ruthenium Red
Calcineurin
Induced currents
Theoretical Models
Mathematical models
Calcium
Membranes
Imaging techniques
Kinetics

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

Cite this

Enhanced desensitization followed by unusual resensitization in GABAA receptors in phospholipase C-related catalytically inactive protein-1/2 double-knockout mice. / Toyoda, Hiroki; Saito, Mitsuru; Sato, Hajime; Tanaka, Takuma; Ogawa, Takeo; Yatani, Hirofumi; Kawano, Tsutomu; Kanematsu, Takashi; Hirata, Masato; Kang, Youngnam.

In: Pflugers Archiv European Journal of Physiology, Vol. 467, No. 2, 01.01.2014, p. 267-284.

Research output: Contribution to journalArticle

Toyoda, Hiroki ; Saito, Mitsuru ; Sato, Hajime ; Tanaka, Takuma ; Ogawa, Takeo ; Yatani, Hirofumi ; Kawano, Tsutomu ; Kanematsu, Takashi ; Hirata, Masato ; Kang, Youngnam. / Enhanced desensitization followed by unusual resensitization in GABAA receptors in phospholipase C-related catalytically inactive protein-1/2 double-knockout mice. In: Pflugers Archiv European Journal of Physiology. 2014 ; Vol. 467, No. 2. pp. 267-284.
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AU - Ogawa, Takeo

AU - Yatani, Hirofumi

AU - Kawano, Tsutomu

AU - Kanematsu, Takashi

AU - Hirata, Masato

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