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Increased Expression of Transient Receptor Potential Vanilloid 4 in Cortical Lesions of Patients with Focal Cortical
Xin Chen1, Fei-Ji Sun1, Yu-Jia Wei1
1Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Aim:
Focal cortical dysplasia (FCD) represents a well-known cause of medically intractable epilepsy. Studies found that transient receptor potential vanilloid receptor 4 (TRPV4) may participate in the occurrence of seizures. This study investigated the expression patterns of TRPV4 in FCD and the cascade that regulate functional state of TRPV4 in cortical neurons.
Methods:
Thirty-nine surgical specimens from FCD patients and 10 age-matched control samples from autopsies were included in this study. Protein expression and distribution were detected by Western blot, immunohistochemistry, and immunofluorescence staining. Calcium imaging was used to detect the TRPV4-mediated Ca(2+) influx in cortical neurons.
Results:
(1) The protein levels of TRPV4 and of an upstream factor, protein kinase C (PKC), were markedly elevated in FCD. (2) TRPV4 staining was stronger in the dysplastic cortices of FCD and mainly observed in neuronal microcolumns and malformed cells. (3) The activation of TRPV4 was central for [Ca(2+)]i elevation in cortical neurons, and this activity of TRPV4 in cortical neurons was regulated by the PKC, but not the PKA, pathway.
Conclusion:
The overexpression and altered cellular distribution of TRPV4 in FCD suggest that TRPV4 may potentially contribute to the epileptogenesis of FCD.
Insights
Overexpression of TRPV4 channels in focal cortical dysplasia (FCD) may contribute to epilepsy. Protein kinase C (PKC) regulates TRPV4 activation, suggesting a potential therapeutic target for intractable seizures.
Area of Science:
- Neuroscience
- Epileptology
- Molecular Biology
Background:
- Focal cortical dysplasia (FCD) is a leading cause of intractable epilepsy.
- Transient receptor potential vanilloid receptor 4 (TRPV4) has been implicated in seizure occurrence.
Purpose of the Study:
- Investigate TRPV4 expression patterns in FCD.
- Elucidate the regulatory cascade of TRPV4 in cortical neurons.
Main Methods:
- Western blot, immunohistochemistry, and immunofluorescence on FCD and control samples.
- Calcium imaging to assess TRPV4-mediated calcium influx in cortical neurons.
Main Results:
- Markedly elevated TRPV4 and protein kinase C (PKC) levels in FCD.
- Enhanced TRPV4 staining in dysplastic cortices, particularly in neuronal microcolumns and malformed cells.
- PKC, not PKA, pathway regulates PKC-mediated TRPV4 activation and subsequent calcium influx.
Conclusions:
- TRPV4 overexpression and altered distribution in FCD suggest a role in epileptogenesis.
- Targeting the TRPV4/PKC pathway may offer a therapeutic strategy for FCD-related epilepsy.
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