During intense (but still physiological) neuronal activity the extracellular potassium concentration may rise almost twice, from 2-2.5 mM to 4-4.2 mM; such an increase can be observed, for example, in the cat spinal cord during rhythmic and repetitive flexion/extension of the knee joint. As a rule, however, during regular physiological activity in the CNS the [K+]o rarely increases by more than 0.2 to 0.4 mM. Nonetheless, locally, in tiny microdomains such as for instance occurring in narrow clefts between neuronal and astroglial membranes in perisynaptic areas, [K+]o may transiently attain much higher levels. The relatively small rises in [K+]o accompanying physiological neuronal activity indicate that powerful mechanisms controlling extracellular potassium are in operation. Disruption of these mechanisms, which do occur in pathology, results in a profound [K+]o dyshomeostasis; upon epileptic seizures, for example, [K+]o may reach 10-12 mM, while during brain ischaemia and spreading depression [K+]o can transiently peak at 50-60 mM.
The major system which removes K+ from the extracellular space is located in astrocytes and is represented by local K+ uptake and K+ spatial buffering. The local K+ uptake occurs in the individual cells and is mediated by K+ channels and transporters (Figure 7.8). The resting membrane potential (Vm) of astrocytes (~ -90 mV) is determined almost exclusively by high K+ permeability of glial plasmalemma and therefore it is very close to the K+ equilibrium potential, EK. Increases in [K+]o would instantly shift the EK towards depolarization, which would generate an inflow of K+ ions (as the Vm < EK). However, this inward K+ current rapidly depolarizes the membrane and soon Vm becomes equal to EK, and K+ influx ceases. Therefore, K+ channels contribute only a little towards local K+ uptake. Most of it is accomplished via Na/K pumps and Na/K/Cl transporters. The Na/K pump expels Na+ out of the cell and brings K+ into it. The glial Na/K pumps are specifically designed for the removal of K+ from the extracellular space when [K+ ]o is increased, as they saturate at around 10-15 mM [K+ ]o; in contrast neuronal Na/K pumps are fully saturated already at 3 mM [K+]o. In addition, K+ uptake is assisted by Na/K/Cl cotransport, in which Cl- influx balances K+ entry. However, the capacity for local K+ uptake is rather limited, because it is accompanied with an overall increase in intracellular K+ concentration; water follows and enters the cells, resulting in their swelling.
A much more powerful and widespread mechanism for the removal of excess extracellular K+ is spatial buffering, a model proposed in the 1960s by Wolfgang Walz and Richard Orkand. In this case, K+ ions entering a single cell are redistributed throughout the glial syncytium by intercellular K+ currents through gap junctions. After this spatial redistribution, K+ ions are expelled into either the
Figure 7.8 Astrocytes provide for local and spatial potassium buffering: Buffering of extracellular potassium occurs through astroglial inward rectifier potassium channels Kjr (local potassium buffering). Potassium is released into the extracellular space during neuronal activity (K+ efflux underlies the recovery phase - repolarization - of the action potential). Astrocytes take up excess K+ through K^r, redistribute the K+ through the astroglial syncytium via gap junctions (spatial potassium buffering), and release K+ through K^r. See the text for further details
Figure 7.8 Astrocytes provide for local and spatial potassium buffering: Buffering of extracellular potassium occurs through astroglial inward rectifier potassium channels Kjr (local potassium buffering). Potassium is released into the extracellular space during neuronal activity (K+ efflux underlies the recovery phase - repolarization - of the action potential). Astrocytes take up excess K+ through K^r, redistribute the K+ through the astroglial syncytium via gap junctions (spatial potassium buffering), and release K+ through K^r. See the text for further details interstitium or perivascular space, where they are removed into the blood. In spatial, K+ buffering, the K+ ions are transported across the membranes through K+ channels. Local K+ entry depolarizes the cell, which creates an electrical and chemical gradient between this cell and neighbouring astrocytes connected via gap junctions. This provides the force for K+ ions to diffuse into the syncytium, preventing local membrane depolarization (thus maintaining K+ influx) and dispersing K+ ions through many cells, so that the actual elevation in cytoplasmic K+ concentration is minimal (Figure 7.8). The principal K+ channels responsible for spatial buffering are inwardly rectifying channels of K;r4.1 type. These channels are only mildly rectifying; i.e. they allow both inward and outward K+ movements at the resting membrane potential levels. This is important, as K+ is finally expelled from the glial syncytium also through the Kir channels. Another important feature of Kir channels is that their conductance is directly regulated by the [K+]o levels; the conductance increases as a square root of increase in [K+]o. In other words, local increases in [K+]o augments the rate of K+ accumulation of glial cells. The K channels are clustered in perisynaptic processes of astroglial cells and in their endfeet (where the density of K channels can be up to 10 times larger that in the rest of the cell membrane). This peculiar distribution facilitates K+ uptake around areas of neuronal activity and K+ extrusion directly into the vicinity of blood vessels.
Sometimes, K+ spatial buffering may take place within the confines of an individual glial cell. A particular example of this process, known as K+ siphoning, was described in retinal Müller cells by Eric Newman in the 1980s (Figure 7.9). Müller cells have contacts with virtually all the cellular elements of the retina. The main endfoot of the Müller cell closely apposes the vitreous space, whereas the apical part projects into the subretinal space; Müller cells also send perivascular processes, which enwrap retinal capillaries. Importantly, the endfoot and perivascular processes contain very high densities of K channels. Potassium buffering mediated by Müller cells occurs primarily in the inner plexiform layer of the retina, which contains most of the retinal synapses. The K+ ions released during synaptic activity enter the cytosol of the glial cell, through which they are rapidly equilibrated. Subsequently, the excess of potassium is expelled through K channels located in the endfoot into the vitreous humour or through Kir channels located in perivascular processes into the perivascular space. Some of the K+ ions may also be released through apical processes, where light induces a decrease in [K+]o in the subretinal space.
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