Increased Expression of TRPC5 in Cortical Lesions of the Focal Cortical Dysplasia

Xu, Guang-Zhen; Shu, Hai-Feng; Yue, Hai-Yun; Zheng, Dahai; W, Guo; Yang, Hui

doi:10.1007/s12031-014-0390-8

Cited by 9 publications

(5 citation statements)

References 40 publications

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“…In other words, the localization pattern of the [ 125 I]TZ66127 ARG signal matched well with the pattern of TRPC5 IHC staining signal in the rat brain sections. These results are in agreement with previous findings for TRPC5 region‐specific protein expression . Together, our results clearly demonstrate a widespread distribution of TRPC5‐specific binding sites in the rat brain.…”

Section: Resultssupporting

confidence: 93%

Synthesis and Characterization of a Specific Iodine‐125‐Labeled TRPC5 Radioligand

Liang

et al. 2020

ChemMedChem

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The nonselective Ca 2 +-permeable transient receptor potential channel subfamily member 5 (TRPC5) belongs to the transient receptor potential canonical (TRPC) superfamily and is widely expressed in the brain. Compelling evidence reveals that TRPC5 plays crucial roles in depression and other psychiatric disorders. To develop a TRPC5 radioligand, following up on our previous effort, we synthesized the iodine compound TZ66127 and its iodine-125-labeled counterpart [ 125 I]TZ66127. The synthesis of TZ66127 was achieved by replacing chloride with iodide in the structure of HC608, and the [ 125 I]TZ66127 was radiosynthesized using its corresponding tributylstannylated precursor. We established a stable human TRPC5-overexpressed HEK293-hTRPC5 cell line and performed Ca 2 + imaging and a cell-binding assay study of TZ66127; these indicated that TZ66127 had good inhibition activity for TRPC5, and the inhibitory efficiency of TZ66127 toward TRPC5 presented in a dose-dependent manner. An in vitro autoradiography and immunohistochemistry study of rat brain sections suggested that [ 125 I]TZ66127 had binding specificity toward TRPC5. Altogether, [ 125 I]TZ66127 has high potential to serve as a radioligand for screening the binding activity of other new compounds toward TRPC5. The availability of [ 125 I]TZ66127 might facilitate the development of therapeutic drugs and PET imaging agents that target TRPC5.

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Section: Resultssupporting

confidence: 93%

Synthesis and Characterization of a Specific Iodine‐125‐Labeled TRPC5 Radioligand

Liang

et al. 2020

ChemMedChem

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“…In TRPC5 KO mice, seizure and neuronal cell death induced by pilocarpine was significantly reduced [ 34 ]. In cortical lesions of the focal cortical dysplasia, common intractable epilepsy in both pediatric and adult patients, the expression of TRPC5 is significantly increased in glutamatergic and GABAergic neurons [ 46 ]. Consistently, in our results, TRPC5 mRNA and protein were predominantly expressed in neurons than astrocytes, cell death was dependent to the expression of TRPC5, and NU6027, an inhibitor of TRPC5, reduced neuronal death in cortical cultures.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Zinc-Dependent Delayed Calcium Influx via TRPC5 in Oxidative Neuronal Death and its Prevention by Novel TRPC Antagonist

et al. 2018

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Oxidative stress is a key mediator of neuronal death in acute brain injuries, such as epilepsy, trauma, and stroke. Although it is accompanied by diverse cellular changes, increases in levels of intracellular zinc ion (Zn) and calcium ion (Ca) may play a critical causative role in oxidative neuronal death. However, the mechanistic link between Zn and Ca dyshomeostasis in neurons during oxidative stress is not well-understood. Here, we show that the exposure of cortical neurons to HO led to a zinc-triggered calcium influx, which resulted in neuronal death. The cyclin-dependent kinase inhibitor, NU6027, inhibited HO-induced Ca increases and subsequent cell death in cortical neurons, without affecting the early increase in Zn. Therefore, we attempted to identify the zinc-regulated Ca pathway that was inhibited by NU6027. The expression profile in cortical neurons identified transient receptor potential cation channel 5 (TRPC5) as a candidate that is known to involve in the generation of epileptiform burst firing and epileptic neuronal death (Phelan KD et al. 2012a; Phelan KD et al. 2013b). NU6027 inhibited basal and zinc-augmented TRPC5 currents in TRPC5-overexpressing HEK293 cells. Consistently, cortical neurons from TRPC5 knockout mice were highly resistant to HO-induced death. Moreover, NU6027 is neuroprotective in kainate-treated epileptic rats. Our results demonstrate that TRPC5 is a novel therapeutic target against oxidative neuronal injury in prolonged seizures and that NU6027 is a potent inhibitor of TRPC5.

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“…TRPV channels (e.g., vanilloid receptors and capsaicin receptors) have been shown to play a role in long-term depression in the hippocampus (47) and in glutamate release in the solitary tract nucleus (48). Tissue specimens from patients with type IIb FCDs and TSC show increased expression of TRPV channels, whereas control specimens show little TRPV (49). Electrophysiological studies have demonstrated that activation of these channels produces an increase in Ca 2+ in the cell, but the exact role these channels play in epilepsy and epileptogenesis remains unknown (50).…”

Section: Expression Of Other Cell Surface Receptors and Neuropeptidesmentioning

confidence: 99%

Focal Cortical Dysplasia: Gene Mutations, Cell Signaling, and Therapeutic Implications

Iffland

Crino

2017

Annu. Rev. Pathol. Mech. Dis.

110

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Focal cortical dysplasias (FCDs) are malformations of cortical development (MCDs) that are highly associated with medication-resistant epilepsy and are the most common cause of neocortical epilepsy in children. FCDs are a heterogeneous group of developmental disorders caused by germline or somatic mutations that occur in genes regulating the PI3K/Akt/mTOR pathway-a key pathway in neuronal growth and migration. Accordingly, FCDs are characterized by abnormal cortical lamination, cell morphology (e.g., cytomegaly), and cellular polarity. In some FCD subtypes, balloon cells express proteins typically seen in neuroglial progenitor cells. Because recurrent intractable seizures are a common feature of FCDs, epileptogenic electrophysiological properties are also observed in addition to local inflammation. Here, we will summarize the current literature regarding FCDs, addressing the current classification system, histopathology, molecular genetics, electrophysiology, and transcriptome and cell signaling changes.

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Increased Expression of TRPC5 in Cortical Lesions of the Focal Cortical Dysplasia

Cited by 9 publications

References 40 publications

Synthesis and Characterization of a Specific Iodine‐125‐Labeled TRPC5 Radioligand

Synthesis and Characterization of a Specific Iodine‐125‐Labeled TRPC5 Radioligand

Contribution of Zinc-Dependent Delayed Calcium Influx via TRPC5 in Oxidative Neuronal Death and its Prevention by Novel TRPC Antagonist

Focal Cortical Dysplasia: Gene Mutations, Cell Signaling, and Therapeutic Implications

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