Kir4.1 channels regulate swelling of astroglial processes in experimental spinal cord edema

Abstract

In glial cells, inwardly rectifying K + channels (Kir) control extracellular [K + ] o homeostasis by uptake of K + from the extracellular space and release of K + into the microvasculature. Kir channels were also recently implicated in K + -associated water influx and cell swelling. We studied the time-dependent expression and functional implication of the glial Kir4.1 channel for astroglial swelling in a spinal cord edema model. In this CNS region, Kir4.1 is expressed on astrocytes from the second postnatal week on and co-localizes with aquaporin 4 (AQP4). Swelling of individual astrocytes in response to osmotic stress and to pharmacological Kir blockade were analyzed by time-lapse-two-photon laserscanning microscopy in situ. Application of 30% hypotonic solution induced astroglial soma swelling whereas no swelling was observed on astroglial processes or endfeet. Coapplication of hypotonic solution and Ba 2+ , a Kir channel blocker, induced prominent swelling of astroglial processes. In Kir4.1)/) mice, however, somatic as well as process swelling was observed upon application of 30% hypotonic solutions. No additional effect was provoked upon co-application with Ba 2+ . Our experiments show that Kir channels prevent glial process swelling under osmotic stress. The underlying Kir channel subunit that controls glial process swelling is Kir4.1, whereas changes of the glial soma are not substantially related to Kir4.1.

Analysis of Astroglial K+ Channel Expression in the Developing Hippocampus Reveals a Predominant Role of the Kir4.1 Subunit

“…At the same time, the lacunosum-moleculare is the region with the highest density of perfused microvessels in the hippocampus (Gerhart et al, 1991;Shimada et al, 1992). Kir4.1 is highly expressed around synapses and blood vessels (Higashi et al, 2001;Hibino et al, 2004), and colocalized AQP4 and Kir4.1 channels in astrocytic endfeet touching microvessels mediate coupled transport of K ϩ and water (Nagelhus et al, 2004;Dibaj et al, 2007). The finding of a concerted developmental increase of AQP4 and Kir4.1 in astrocytes and Müller cells further supports their critical involvement in brain water regulation, K ϩ homeostasis, and volume regulation (Wen et al, 1999;Wurm et al, 2006).…”

“…Kir4.1 transcripts were found in all cells tested (n ϭ 39). All astrocytes coexpressed Kir4.1 together with AQP4 (n ϭ 11; data not shown), an astroglial water channel (Nagelhus et al, 2004;Dibaj et al, 2007). Transcripts encoding Kir5.1 were rarely found.…”

Channels and Volume Changes in the Life and Death of the Cell

“…The inwardly rectifying K 1 channels Kir4.1 and Kir4.5, which sense small changes in osmolarity (Grunnet et al, 2003;Soe et al, 2009), colocalize with aquaporin 4 (AQP4) in the glial endfeet of the blood-brain barrier, suggesting that they play a role in swelling and/or volume control in these cells. Kir channels regulate extracellular K 1 homeostasis during the K 1 spatial buffering through the glial syncytium, and this transcellular K 1 transport is accompanied by transmembrane water fluxes, likely via a Kir4.1/AQP4 complex (Nagelhus et al, 1999;Dibaj et al, 2007). The two-pore-domain K 1 channels participate in RVD in lymphocytes, Ehrlich ascites cells, astrocytes, and kidney cells (Niemeyer et al, 2001;Kirkegaard et al, 2010;Andronic et al, 2013).…”

New Insights on Astrocyte Ion Channels: Critical for Homeostasis and Neuron-Glia Signaling

“…In astrocytes, putative functions of Kir4.1 include K ϩ homeostasis, maintenance of the astrocyte resting membrane potential, high astrocyte K ϩ conductance, astrocyte cell volume regulation, and facilitation of glutamate uptake Dibaj et al, 2007;Djukic et al, 2007;Kucheryavykh et al, 2007;Seifert et al, 2009). Increased Kir4.1 expression and function are associated with astrocyte maturation (Seifert et al, 2009), whereas reduced channel expression and/or activity is associated with the CNS pathologies such as epilepsy (Ferraro et al, 2004;Scholl et al, 2009), Alzheimer's disease (Wilcock et al, 2009), amyotrophic lateral sclerosis (Kaiser et al, 2006;Bataveljić et al, 2012), spinal cerebellar ataxia (Magaña et al, 2013), and pain (Vit et al, 2008).…”