Abstract
Aquaporin-4 (AQP4) is the main water channel protein expressed in the central nervous system (CNS). AQP4 is densely expressed in astrocyte end-feet, and is an important factor in CNS water and potassium homeostasis. Changes in AQP4 activity and expression have been implicated in several CNS disorders, including (but not limited to) epilepsy, edema, stroke, and glioblastoma. For this reason, many studies have been done to understand the various ways in which AQP4 is regulated endogenously, and could be regulated pharmaceutically. In particular, four regulatory methods have been thoroughly studied; regulation of gene expression via microRNAs, regulation of AQP4 channel gating/trafficking via phosphorylation, regulation of water permeability using heavy metal ions, and regulation of water permeability using small molecule inhibitors. A major challenge when studying AQP4 regulation is inter-method variability. A compound or phosphorylation which shows an inhibitory effect in vitro may show no effect in a different in vitro method, or even show an increase in AQP4 expression in vivo. Although a large amount of variability exists between in vitro methods, some microRNAs, heavy metal ions, and two small molecule inhibitors, acetazolamide and TGN-020, have shown promise in the field of AQP4 regulation.
Highlights
Aquaporins (AQPs) are a group of selective transmembrane channels which are expressed in every major organ group in the human body [1,2]
Phosphorylation of S276, along with S285, T289, and S316 by casein kinase II (CKII) was shown to be necessary for Golgi transition in mouse primary cultured astrocytes, as mutations at these locations caused mouse AQP4 (mAQP4) to localize to the Golgi bodies and lose the ability to migrate to the membrane in vitro [59]
These results indicate that if phosphorylation by CKII occurs at S276, mAQP4 is freed from the Golgi bodies and able to migrate to the cell membrane, but if the same phosphorylation site is activated by PKA, this directs the cell to internalize human AQP4 (hAQP4) and rat AQP4 (rAQP4) and reduce their expression [58,59,66]
Summary
Aquaporins (AQPs) are a group of selective transmembrane channels which are expressed in every major organ group in the human body [1,2]. While 13 unique AQPs have been identified in the human body far, aquaporin-4 (AQP4) has become an interesting therapeutic target in various neurological disorders, due to its variety of functions and widespread expression in the nervous system [3]. AQP4 is upregulated and redistributed, showing a loss of polarized distribution in the end-feet of high grade tumors [12,20,21,22]. This loss of AQP4 polarity may contribute to increased migration capability of the astrocytoma cells, as AQP4 aggregation state has been shown to have an effect on glioma cell migration [23,24,25]. With the increase in interest in AQP4 as a potential therapeutic target [1,5,16,19], and the implications AQP4 activity has on many neurological disorders [7,14,16,17,18,21,22,23,25,30,31,32,33,34,42,43], it is important to have a clear understanding of the myriad of ways in which AQP4 is known to be regulated
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