The Role of Aquaporins in Epileptogenesis-A Systematic Review

Abstract

Aquaporins (AQPs) are a family of membrane proteins involved in the transport of water and ions across cell membranes. AQPs have been shown to be implicated in various physiological and pathological processes in the brain, including water homeostasis, cell migration, and inflammation, among others. Epileptogenesis is a complex and multifactorial process that involves alterations in the structure and function of neuronal networks. Recent evidence suggests that AQPs may also play a role in the pathogenesis of epilepsy. In animal models of epilepsy, AQPs have been shown to be upregulated in regions of the brain that are involved in seizure generation, suggesting that they may contribute to the hyperexcitability of neuronal networks. Moreover, genetic studies have identified mutations in AQP genes associated with an increased risk of developing epilepsy. Our review aims to investigate the role of AQPs in epilepsy and seizure onset from a pathophysiological point of view, pointing out the potential molecular mechanism and their clinical implications.

Keywords: AQP4; aquaporins; epilepsy; ion homeostasis; pathophysiology; seizure.

Figure 1

Anchoring system of AQP4 in CNS. The dystrophin complex is connected to the basal lamina, and it interacts with AQP4 via α-syntrophin (α-syn) or other syntrophins (syn). It is hypothesized that α-syn plays a crucial role in anchoring the M23 isoform of AQP4, which is responsible for forming orthogonal arrays of proteins, particularly concentrated in endfeet membranes.

Figure 2

PRISMA flow chart.

Figure 3

In stress conditions, such as after an injury (hypoxic insult), astrocyte CaM is activated and interacts with adenylyl cyclase, activating in turn cyclic AMP (cAMP)-dependent PKA, which phosphorylates AQP4 at Ser276, determining its displacement to the plasma membrane. CaM interacts directly with AQP4, driving AQP4 to subcellular mislocalization and disrupting its physiological homeostasis.