Regulation of GABAA-Receptor Surface Expression With Special Reference to the Involvement of GABARAP (GABAA Receptor-Associated Protein) and PRIP (Phospholipase C-Related, but Catalytically Inactive Protein)

Kanematsu, Takashi; Mizokami, Akinari; Watanabe, Keiko; Hirata, Masato

doi:10.1254/jphs.cp0070063

Cited by 40 publications

(27 citation statements)

References 42 publications

(58 reference statements)

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“…The upregulation of GnRH secretion in DKO mice might be the cause for the higher levels of LH and FSH in accordance with the hierarchy, but this could not be experimentally qualified because it is difficult to measure serum levels of GnRH streaming in the hypophysial portal system. GnRH neurons were reported to be modulated by activities of GABA A receptors [32], the properties of which have been altered in DKO mice [18,33]. In cases of either dependence on or independence of GnRH, the upregulation of secretion from pituitary glands would be more probable.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Phospholipase C-Related Inactive Protein in the Mouse Reproductive System Through the Regulation of Gonadotropin Levels1

Matsuda¹,

Tsutsumi²,

Kanematsu³

et al. 2009

Biology of Reproduction

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Phospholipase C-related but catalytically inactive protein (comprising PRIP-1 and PRIP-2 [officially designated PLCL1 and PLCL2]) was first identified in our laboratory, but the biological functions have remained elusive. Therefore, we generated Plcl1 and Plcl2 double-knockout mice (Plcl1(tm1Mh); Plcl2(tm1Tta)) to gain insight into the biological function. Double-knockout mice apparently grew normally and became fertile; however, during animal maintenance, we noticed that mutant couples exhibited decreased litter events and litter size, indicating dysfunction of the reproductive system. Cross-mating experiments to discriminate whether males or females were defective indicated that the cause appeared to be on the female side. Mutant female mice had an apparently smaller uterus by gross anatomical observation and had more estrous days during the cycles. Levels of serum luteinizing hormone (LH) and follicle-stimulating hormone were measured for 5-6 consecutive days and were significantly higher in the mutant, which was also confirmed by examining the secretion of LH from the explant culture of anterior pituitary glands of wild-type and double-knockout mice. These results suggest that through gonadotropin secretion, PRIP plays an important role in female reproduction.

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Section: Discussionmentioning

confidence: 99%

Involvement of Phospholipase C-Related Inactive Protein in the Mouse Reproductive System Through the Regulation of Gonadotropin Levels1

Matsuda¹,

Tsutsumi²,

Kanematsu³

et al. 2009

Biology of Reproduction

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“…We also have reported that PRIP modulates brain-derived neurotrophic factor (BDNF)-induced GABA A receptor endocytosis through the regulation of the receptor phosphorylation level (29). These results suggest that PRIP regulates GABA A receptor function through receptor trafficking, phosphorylation, and endocytosis (30,31).…”

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confidence: 89%

Phospholipase C-related but Catalytically Inactive Protein Is Required for Insulin-induced Cell Surface Expression of γ-Aminobutyric Acid Type A Receptors

Fujii

Kanematsu

Ishibashi

et al. 2010

Journal of Biological Chemistry

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The ␥-aminobutyric acid type A (GABA A ) receptors play a pivotal role in fast synaptic inhibition in the central nervous system. One of the key factors for determining synaptic strength is the number of receptors on the postsynaptic membrane, which is maintained by the balance between cell surface insertion and endocytosis of the receptors. In this study, we investigated whether phospholipase C-related but catalytically inactive protein (PRIP) is involved in insulin-induced GABA A receptor insertion. Insulin potentiated the GABA-induced Cl ؊ current (I GABA ) by about 30% in wild-type neurons, but not in PRIP1 and PRIP2 double-knock-out (DKO) neurons, suggesting that PRIP is involved in insulin-induced potentiation. The phosphorylation level of the GABA A receptor ␤-subunit was increased by about 30% in the wild-type neurons but not in the mutant neurons, which were similar to the changes observed in I GABA . We also revealed that PRIP recruited active Akt to the GABA A receptors by forming a ternary complex under insulin stimulation. The disruption of the binding between PRIP and the GABA A receptor ␤-subunit by PRIP interference peptide attenuated the insulin potentiation of I GABA . Taken together, these results suggest that PRIP is involved in insulin-induced GABA A receptor insertion by recruiting active Akt to the receptor complex.The ␥-aminobutyric acid (GABA) 4 type A (GABA A ) receptors are GABA-gated chloride channels that mediate the majority of fast synaptic inhibition in the central nervous system(1-5). The perturbation of GABA-GABA A receptors-mediated neurotransmission causes several central nervous system disorders including motor coordination, anxiety, insomnia, schizophrenia, and epilepsy. Additionally, GABA A receptors are important therapeutic drug targets for sedative, anxiolytic, anticonvulsant, and hypnotic agents (1-5). Therefore, it is important to uncover how synaptic strength is regulated in GABAergic transmission. The GABA A receptors are heteropentamers composed of a combination of 18 GABA A receptor subunits, which are divided into seven subunit classes (␣1-6, ␤1-3, ␥1-3, ␦, ⑀1-3, , and ) based on their sequence homology (1-5). Each receptor subunit has a similar structure with a large N-terminal extracellular region, which is the binding site for GABA and psychoactive drugs such as benzodiazepines, followed by four hydrophobic transmembrane domains (TM1-4) with a large intracellular loop region between TM3 and 4. This intracellular loop region is a target for proteinprotein interactions, phosphorylation, ubiquitination, and palmitoylation, which control receptor trafficking, stability, and clustering on the synaptic membrane (1-5). Regulation of the number of receptors on the postsynaptic membrane is one of the key factors for determining synaptic strength, which is maintained by a balance between the insertion and endocytosis of receptors to/from the cell surface. Recently, it was reported that the dephosphorylation of the GABA A receptor ␤-or ␥2-subunit triggers endocytosis by f...

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“…Gamma-amino butyric acid receptors (GABA-A) mediate fast synaptic inhibition in the brain and spinal cord (14). Alterations in neuronal surface receptors modulate the synaptic strength, leading to changes in sensitivity to neurotransmitters (15). When a similar network analysis was performed for the 193 control proteins,…”

Section: Proteins Associated With Ic/pbsmentioning

confidence: 99%

Urinary proteomics evaluation in interstitial cystitis/painful bladder syndrome: a pilot study

et al. 2010

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Purpose: Interstitial cystitis/painful bladder syndrome (IC/PBS) is characterized by chronic pain, pressure and discomfort felt in the pelvis or bladder. An in-depth shotgun proteomics study was carried out to profile the urinary proteome of women with IC/PBS to identify possible specific proteins and networks associated with IC/PBS. Materials and Methods: Urine samples from ten female IC/PBS patients and ten female asymptomatic, healthy control subjects were analyzed in quadruplicate by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on a hybrid linear ion trap-orbitrap mass spectrometer. Gas-phase fractionation (GPF) was used to enhance protein identification. Differences in protein quantity were determined by peptide spectral counting. Results: α-1B-glycoprotein (A1BG) and orosomucoid-1 (ORM1) were detected in all IC/PBS patients, and ≥ 60% of these patients had elevated expression of these two proteins compared to control subjects. Transthyretin (TTR) and hemopexin (HPX) were detected in all control individuals, but ≥ 60% of the IC/PBS patients had decreased expression levels of these two proteins. Enrichment functional analysis showed cell adhesion and response to stimuli were down-regulated whereas response to inflammation, wounding, and tissue degradation were up-regulated in IC/PBS. Activation of neurophysiological processes in synaptic inhibition, and lack of DNA damage repair may also be key components of IC/PBS. Conclusion: There are qualitative and quantitative differences between the urinary proteomes of women with and without IC/PBS. We identified a number of proteins as well as pathways/networks that might contribute to the pathology of IC/PBS or result from perturbations induced by this condition.

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Regulation of GABAA-Receptor Surface Expression With Special Reference to the Involvement of GABARAP (GABAA Receptor-Associated Protein) and PRIP (Phospholipase C-Related, but Catalytically Inactive Protein)

Cited by 40 publications

References 42 publications

Involvement of Phospholipase C-Related Inactive Protein in the Mouse Reproductive System Through the Regulation of Gonadotropin Levels1

Involvement of Phospholipase C-Related Inactive Protein in the Mouse Reproductive System Through the Regulation of Gonadotropin Levels1

Phospholipase C-related but Catalytically Inactive Protein Is Required for Insulin-induced Cell Surface Expression of γ-Aminobutyric Acid Type A Receptors

Urinary proteomics evaluation in interstitial cystitis/painful bladder syndrome: a pilot study

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