Channels and Transporters in Astrocyte Volume Regulation in Health and Disease

Abstract

Astrocytes are the second most abundant cell type in the central nervous system and serve various functions, many of which maintain homeostasis of the intracellular milieu in the face of constant change. In order to accomplish these important functions, astrocytes must regulate their cell volume. In astrocytes, cell volume regulation involves multiple channels and transporters, including AQP4, TRPV4, TRPM4, VRAC, Na+/K+ ATPase, NKCC1 and Kir4.1. AQP4 is a bidirectional water channel directly involved in astrocyte cell volume regulation. AQP4 also forms heteromultimeric complexes with other channels and transporters involved in cell volume regulation. TRPV4, a mechanosensitive channel in involved in osmotic regulation in various cell types, forms a complex with AQP4 to decrease cell volume in response to cell swelling. TRPM4 also forms a complex with AQP4 and SUR1 in response to injury resulting in cell swelling. Another complex forms between Na+/K+ ATPase, AQP4, and mGluR5 to regulate the perisynaptic space. NKCC1 is a co-transporter involved in cell volume increases either independently through cotransport of water or a functional interaction with AQPs. VRAC is implicated in regulatory volume decreases and may also functionally interact with AQP4. Although Kir4.1 colocalizes with AQP4, its role in cell volume regulation is debated. In diseases where fluid/electrolyte homeostasis is disturbed such as stroke, ischemic injury, inflammation, traumatic brain injury and hydrocephalus, cell volume regulation is challenged, sometimes past the point of recovery. Thus, a greater understanding of signaling pathways which regulate transport proteins as well as the functional and physical interactions that exist between transporters will provide a basis for the development of pharmaceutical targets to treat these prevalent and often devastating diseases.

Insight into the Mammalian Aquaporin Interactome

“…Transient Receptor Potential Vanilloid 4 (TRPV4) has been shown to interact with rAQP4, mAQP4 and hAQP4 and the AQP4–TRPV4 complex may play an essential role in the hypotonicity-induced increase in intracellular calcium and inhibition of regulatory volume decrease [ 119 ]. Indeed, based on experimental data, it has been postulated that AQP4-mediated water flux activates TRPV4 and, reciprocally, calcium entry through TRPV4 modulates AQP4-mediated water movement [ 120 , 121 ]. AQP4 has also been shown to interact with another member of the TRP family, TRPM4 (Transient Receptor Potential Cation Channel Subfamily M Member 4 (TRPM4), a non-selective monovalent cation channel activated by intracellular calcium [ 122 ].…”

“…AQP4 has also been shown to interact with another member of the TRP family, TRPM4 (Transient Receptor Potential Cation Channel Subfamily M Member 4 (TRPM4), a non-selective monovalent cation channel activated by intracellular calcium [ 122 ]. Together with Sulfonylurea receptor 1 (SUR1), an ATP-binding cassette transporter regulating pore-forming units [ 123 ], AQP4 and TRPM4 may form a ternary complex that is involved in cell volume regulation [ 121 , 123 ]. A model of the SUR1–TRPM4–AQP4 complex has been proposed in which four TRPM4 subunits are surrounded by four SUR1 subunits, with four AQP4 tetramers intercalated in between [ 123 , 124 ], although this remains to be confirmed by structural studies.…”

“…SUR1 binding to TRPM4 increased its intracellular calcium sensitivity, contributing to an augmentation of the role of TRPM4 as a negative regulator of intracellular calcium influx, an effect that was further amplified by water influx through AQP4, thereby further diluting the calcium concentration [ 124 ]. Studies have shown that TRPM4-knockout mice displayed altered cell volume regulation involving AQP4 [ 121 , 123 ], and the co-expression of TRPM4 and AQP4 did not result in higher water flow, unlike the co-expression of SUR1, TRPM4 and AQP4 [ 123 ]. Interestingly, CNS injury has been proposed to cause AQP4 to switch interaction partners, from TRPV4 under normal physiological conditions to SUR1–TRPM4, forming a water/ion channel complex that drives edema formation [ 123 ].…”

The CaMKII/MLC1 Axis Confers Ca2+-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes

“…In the central nervous system (CNS), ion and water movements are strictly controlled by astrocytes, the glial cell population mainly responsible for the maintenance of tissue homeostasis and ensuring correct brain functionality [ 1 , 2 , 3 ]. Alterations of these regulative processes can lead to serious complications, due to brain water accumulation and edema formation, as observed in several CNS injuries such as ischemia, trauma, infection, tumors, and inflammation [ 3 , 4 , 5 ]. The astrocyte’s favorable morphological structure and anatomical distribution, with end-foot processes contacting blood vessels, allow these cells to connect parenchymal tissue to the blood circulation, thus favoring the uptake and removal of accumulating solutes and water [ 2 , 6 ].…”

“…The astrocyte’s favorable morphological structure and anatomical distribution, with end-foot processes contacting blood vessels, allow these cells to connect parenchymal tissue to the blood circulation, thus favoring the uptake and removal of accumulating solutes and water [ 2 , 6 ]. To accomplish this task, astrocytes also express a large number of transporters and ion channel proteins [ 1 , 5 , 6 , 7 ]. Understanding how these molecules interplay would greatly help identify potential targets to treat the devastating consequences of brain edema [ 8 ].…”