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Review
. 2004;129(4):1045-56.
doi: 10.1016/j.neuroscience.2004.06.008.

Potassium buffering in the central nervous system

P Kofuji  1 , E A Newman
Affiliations
Review

Potassium buffering in the central nervous system

P Kofuji et al. Neuroscience. 2004.

Abstract

Rapid changes in extracellular K+ concentration ([K+](o)) in the mammalian CNS are counteracted by simple passive diffusion as well as by cellular mechanisms of K+ clearance. Buffering of [K+](o) can occur via glial or neuronal uptake of K+ ions through transporters or K+-selective channels. The best studied mechanism for [K+](o) buffering in the brain is called K+ spatial buffering, wherein the glial syncytium disperses local extracellular K+ increases by transferring K+ ions from sites of elevated [K+](o) to those with lower [K+](o). In recent years, K+ spatial buffering has been implicated or directly demonstrated by a variety of experimental approaches including electrophysiological and optical methods. A specialized form of spatial buffering named K+ siphoning takes place in the vertebrate retina, where glial Muller cells express inwardly rectifying K+ channels (Kir channels) positioned in the membrane domains near to the vitreous humor and blood vessels. This highly compartmentalized distribution of Kir channels in retinal glia directs K+ ions from the synaptic layers to the vitreous humor and blood vessels. Here, we review the principal mechanisms of [K+](o) buffering in the CNS and recent molecular studies on the structure and functions of glial Kir channels. We also discuss intriguing new data that suggest a close physical and functional relationship between Kir and water channels in glial cells.

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Figures

Fig. 1
Fig. 1
Changes in [K+]o in the cat striate cortex and frog retina with enhanced neuronal activity. (A) Upper trace. Dynamic [K+]o changes in the cat striate cortex upon stimulation of the receptive field of hypercomplex cells. [K+]o changes were measured with a double-barreled K+-sensitive microelectrode. Arrows represent bars of light moving down or up in a cell’s receptive field. The 1 mV scale bar corresponds to approximately 0.17 mM. Lower trace. Spike activity recorded in the reference barrel of the K+-sensitive microelectrode. [From Singer and Lux (1975) with permission.] (B) [K+]o changes within layers of the frog retina. A 2-s light stimulus evokes [K+]o increases in the inner plexiform layer (IPL) and outer plexiform layer (OPL) and decreases of [K+]o in the subretinal space (ROS). [From Karwoski et al. (1985), with permission.]
Fig. 2
Fig. 2
Diagram depicting the role of glial cells in [K+]o homeostasis. Top: Glial cells are electrically coupled via gap junctions forming a functional syncytium. With [K+]o equaling 3 mM, the glial syncytium has a membrane potential of approximately −90 mV. (A) Net K+ uptake mechanism. When [K+]o is increased, glial cells accumulate K+ either by the activity of a Na,K–ATPase or by a pathway in which K+ is cotranported with Cl−. In this mechanism of [K+]o regulation, the membrane potential in the glial syncytium is spatially uniform at −56 mV. (B) K+ spatial buffering mechanism. Local increases of [K+]o produce a glial depolarization that spreads through the glial syncytium. The local difference in Vm and EKdrives the K+ uptake in regions of elevated [K+]o and K+ outflow at distant regions. The intracellular currents are carried by K+ and extracellular currents are mediated by other ions such as Na+. [From Orkand (1986), with permission.]
Fig. 3
Fig. 3
Differential roles of Na,K–ATPase pumps and Kir channels for the [K+]o regulation in rat hippocampus slice. (A) In control condition, 3-Hz antidromic stimulation induces a rise of [K+]o in area CA3 that peaks at approximately 5.5 mM followed by a decline to approximately 4.7 mM. With addition of the sodium pump inhibitor di-hydro-ouabain (DHO), the baseline [K+]o increases to approximately 5.1 mM. Antidromic stimulation (3-Hz) induces a rise of [K+]o to approximately 5.9 mM but there is no [K+]o recovery phase. Also absent is the undershoot of [K+]o following the stimulation period. In the inset the two traces are shown superimposed, and the baseline is zeroed. (B) In control condition, 3-Hz antidromic stimulation induced a rise of [K+]o that peaked at approximately 5.2 mM followed by an undershoot in [K+]o. With Ba2+ (200 μM) in the bath, baseline [K+]o increased in relation to control levels and the undershoot in [K+]o following antidromic stimulation is more pronounced. In the inset the two traces are shown superimposed, and the baseline is zeroed. [From D’Ambrosio (2002), with permission.]
Fig. 4
Fig. 4
Evidences for K+ spatial buffering in the rat cortex. (A) Image of the brain slice viewed with darkfield optics. (B1–4) Time course of IOS changes upon neuronal stimulation in middle cortical layers. Red colors represent IOS increases while blue colors represent IOS decreases. These correspond, respectively, to shrinkage and widening of the extracellular space. Notice the extracellular space shrinkage in the middle cortical layers and widening in the most superficial and deep cortical layers as predicted for a K+ spatial buffering mechanism. (C) Time course of extracellular space widening in the cortical layer I measured independently validates the interpretation of IOS. (D) Time course of [K+]o increase in layer I. (E) Time course of [K ]o increase in layer I (blue) and in layer IV (red). [From Holthoff and Witte (2000), with permission.]
Fig. 5
Fig. 5
K+ siphoning in the retina. K+ released in the inner plexiform layer (IPL) upon neuronal stimulation enters the principal glial cell of retina (Müller cell). K+ leaves the glial cell preferentially from the endfoot processes enveloping blood vessels and the vitreal endfoot, as K+ conductance is maximal in these membrane regions. Light-evoked [K+ efflux from apical processes. [From Newman ]o decrease in the subretinal space (SRS) lead to K (1996b), with permission.]
Fig. 6
Fig. 6
Kir4.1 channel localization in wild type and mdx3Cv (dystrophin knockout) mouse retinal sections. (A) Kir4.1 is concentrated at the inner limiting membrane (arrow) and to processes around blood vessels (arrowheads) in wild-type retina. (B) In the mdx3Cv mouse, Kir4.1 is more evenly distributed throughout the retina with a reduction in staining at the inner limiting membrane (arrow) and no apparent enrichment of Kir4.1 around blood vessels (arrowheads). The Müller-specific marker glutamine synthetase (C, D), and merged images (E, F) suggest the localization of Kir4.1 to Müller cells. Scale bar = 25 μm (A). [From Connors and Kofuji (2002), with permission.]
Fig. 7
Fig. 7
Schematic representation of the glial cell DGC and associated Kir and water channels. The complex is shown with the putative interactions between a syntrophin isoform, Kir4.1 and AQP4. [From Kofuji and Connors (2003), with permission.]
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