更新于：2024-11-01

CACNA2D2 x CACNA2D1 x GABAA receptor

更新于：2024-11-01

基本信息

关联

项与 CACNA2D2 x CACNA2D1 x GABAA receptor 相关的药物

Pregabalin arenacarbil

靶点

CACNA2D1 x CACNA2D2 x GABAA receptor

作用机制

CACNA2D1调节剂 [+2]

在研机构-

原研机构

XenoPort, Inc.

在研适应症-

非在研适应症

糖尿病周围神经病变 [+3]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 CACNA2D2 x CACNA2D1 x GABAA receptor 相关的临床结果

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100 项与 CACNA2D2 x CACNA2D1 x GABAA receptor 相关的转化医学

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0 项与 CACNA2D2 x CACNA2D1 x GABAA receptor 相关的专利（医药）

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项与 CACNA2D2 x CACNA2D1 x GABAA receptor 相关的文献（医药）

Frontiers in Neuroscience3区 · 医学

Temporal Changes of Spinal Transcriptomic Profiles in Mice With Spinal Nerve Ligation

3区 · 医学

ArticleOA

作者: Zhang, Piao ; Li, Xiang-Yao ; Chen, Gang ; Chen, Ye-Ru ; Yu, Hong ; Wang, Yong-Jie ; Lin, Xian-Yi

Neuropathic pain (NP) is an intractable disease accompanying with allodynia, hyperalgesia and spontaneous pain. Accumulating evidence suggested that large volume of neurotransmitters, genes, and signaling pathways were implicated with the initiation and development of NP, while the underlying mechanism still remained poorly understood. Therefore, it was extremely important to further elucidate the potential regulatory networks for developing appropriate treatment options. Here, the RNA-Seq high-throughput sequencing was employed to determine the genes expression change in mice undergoing spinal nerve ligation (SNL). Meanwhile, the differentially expressed genes (DEGs) were analyzed by using integrated Differential Expression and Pathway analysis (iDEP) tools and String database. Then, quantitative real-time PCR (qRT-PCR) was employed to detect the expression of hub gens. The results showed that the DEGs mainly comprised 1712 upregulated and 1515 downregulated genes at 7 days, and consisted of 243 upregulated and 357 downregulated genes at 28 days after surgery, respectively. Additionally, 133 genes and two pathways including retrograde endocannabinoid signaling and cardiac muscle contraction collectively participated in biological reactions of 7th and 28th day after operation. Moreover, the results showed that the mRNA and protein expression of Ccl5, Cacna2d1, Cacna2d2, Cacnb2, Gabrb3, GluA1, and GluA2 were significantly upregulated in SNL-7/28d group than that of in Sham-7/28d group (SNL-7d vs. Sham-7d; SNL-28d vs. Sham-28d; P < 0.05). And the level of Glra2, Glra4, Glra3, Grik1, Grik2, NR1, NR2A, and NR2B was obviously increased in SNL-7d group compared to Sham-7d group (P < 0.05), but which was no statistical difference between SNL-28d group and Sham-28d group. Therefore, these results provided new perspectives and strategies for deeply illuminating the underlying mechanism, and identifying the key elements for treating NP.

Journal of Neurochemistry

A biallelic mutation in CACNA2D2 associated with developmental and epileptic encephalopathy affects calcium channel‐dependent as well as synaptic functions of α₂δ‐2

Article

作者: Tuluc, Petronel ; Ablinger, Cornelia ; Haddad, Sabrin ; Ortner, Nadine J. ; Campiglio, Marta ; Hessenberger, Manuel ; Obermair, Gerald J. ; Stanika, Ruslan

Abstractα2δ proteins serve as auxiliary subunits of voltage‐gated calcium channels and regulate channel membrane expression and current properties. Besides their channel function, α2δ proteins regulate synapse formation, differentiation, and synaptic wiring. Considering these important functions, it is not surprising that CACNA2D1‐4, the genes encoding for α2δ‐1 to ‐4 isoforms, have been implicated in neurological, neurodevelopmental, and neuropsychiatric disorders. Mutations in CACNA2D2 have been associated with developmental and epileptic encephalopathy (DEE) and cerebellar atrophy. In our present study, we performed a detailed functional characterization of the p.R593P mutation in α2δ‐2, a homozygous mutation previously identified in two siblings with DEE. Importantly, we analyzed both calcium channel‐dependent as well as synaptic functions of α2δ‐2. Our data show that the corresponding p.R596P mutation in mouse α2δ‐2 drastically decreases membrane expression and synaptic targeting of α2δ‐2. This defect correlates with altered biophysical properties of postsynaptic CaV1.3 channel but has no effect on presynaptic CaV2.1 channels upon heterologous expression in tsA201 cells. However, homologous expression of α2δ‐2_R596P in primary cultures of hippocampal neurons affects the ability of α2δ‐2 to induce a statistically significant increase in the presynaptic abundance of endogenous CaV2.1 channels and presynaptic calcium transients. Moreover, our data demonstrate that in addition to lowering membrane expression, the p.R596P mutation reduces the trans‐synaptic recruitment of GABAA receptors and presynaptic synapsin clustering in glutamatergic synapses. Lastly, the α2δ‐2_R596P reduces the amplitudes of glutamatergic miniature postsynaptic currents in transduced hippocampal neurons. Taken together, our data strongly link the human biallelic p.R593P mutation to the underlying severe neurodevelopmental disorder and highlight the importance of studying α2δ mutations not only in the context of channelopathies but also synaptopathies.

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