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. 2022 Jun 6:16:900588.
doi: 10.3389/fncel.2022.900588. eCollection 2022.

Mechanisms Underlying Aquaporin-4 Subcellular Mislocalization in Epilepsy

Jenny I Szu  1 , Devin K Binder  1
Affiliations

Mechanisms Underlying Aquaporin-4 Subcellular Mislocalization in Epilepsy

Jenny I Szu et al. Front Cell Neurosci. .

Abstract

Epilepsy is a chronic brain disorder characterized by unprovoked seizures. Mechanisms underlying seizure activity have been intensely investigated. Alterations in astrocytic channels and transporters have shown to be a critical player in seizure generation and epileptogenesis. One key protein involved in such processes is the astrocyte water channel aquaporin-4 (AQP4). Studies have revealed that perivascular AQP4 redistributes away from astrocyte endfeet and toward the neuropil in both clinical and preclinical studies. This subcellular mislocalization significantly impacts neuronal hyperexcitability and understanding how AQP4 becomes dysregulated in epilepsy is beginning to emerge. In this review, we evaluate the role of AQP4 dysregulation and mislocalization in epilepsy.

Keywords: aquaporin-4; astrocytes; epilepsy; seizures; subcellular localization.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic of AQP4 subcellular mislocalization. (A) After neuronal activation, water enters astrocytes (along with other ions and neurotransmitters such as K+ and glutamate). Water is then transported into nearby blood vessels via perivascular AQP4, overall maintaining water homeostasis. (B) During epilepsy, perivascular AQP4 (M23-AQP4) is lost due to loss of its anchoring protein α-syntrophin (not shown). Additionally, the rapid influx of water activates vasopressin receptors leading to phosphorylation of AQP4 by PKC followed by internalization and subsequent degradation of AQP4. Swelling of astrocytes occurs, resulting in impaired cell volume regulation and further increasing neuronal hyperexcitability.
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