Potassium spatial buffering

Potassium Spatial Buffering is a mechanism for the regulation of extracellular potassium concentration by astrocytes. Other mechanisms for astrocytic potassium clearance are carrier-operated or channel-operated potassium chloride uptake. The depolarization of neurons tends to raise potassium concentration in the extracellular fluid. If a significant rise occurs, it will interfere with neuronal signaling by depolarizing neurons. Astrocytes have large numbers of potassium ion channels facilitating removal of potassium ions from the extracellular fluid. They are taken up at one region of the astrocyte and then distributed throughout the cytoplasm of the cell, and further to its neighbors via gap junctions. This keeps extracellular potassium at levels that prevent interference with normal propagation of an action potential.

Potassium Spatial Buffering

Glial cells have numerous functions in the brain, including clearance of neurotransmitter from the synapses, guidance during neuronal migration, control of neuronal synaptic transmission, and maintaining ideal ionic environment for active communications between neurons in central nervous system. Neurons are surrounded by extracellular fluid rich in sodium ions and poor in potassium ions. The concentrations of these ions are reversed inside the cells. Due to the difference in concentration, there is a chemical gradient across the cell membrane, which leads to sodium influx and potassium efflux. When the action potential takes place, a considerable change in extracellular potassium concentration occurs due to the limited volume of the CNS extracellular space. The change in potassium concentration in extracellular space impacts variety of neuronal processes, such as maintenance of membrane potential, activation and inactivation of voltage gated channels, synaptic transmission, and electrogenic transport of neurotransmitter. Therefore, there are diverse cellular mechanisms for tight control of potassium ions, the most widely accepted mechanisms being K+ spatial buffering mechanism. Orkand and his colleagues who first theorized spatial buffering stated “if a Glial cell becomes depolarized by K+ that has accumulated in the clefts, the resulting current carries K+ inward in the high [K+] region and out again, through electrically coupled Glial cells in low [K+] regions” In the model presented by Orkand and his colleagues, glial cells intake and traverse potassium ions from region of high concentrations to region of low concentration maintaining potassium concentration to be low in extracellular space. Glial cells are well suited for transportation of potassium ions since it has unusually high permeability to potassium ions and traverse long distance by its elongated shape or by being coupled to one another.

Potassium regulatory mechanisms

mechanisms behind potassium buffering can be broadly categorized as either K+ uptake or K+ spatial buffering.

Kir Channel

The high permeability of glial cell membranes to potassium ions are result of expression of high density of potassium selective channels with high open probability at resting membrane potentials. Kir channels, potassium inward rectifying channels, are named after its attributes of allowing the passage of potassium ions inwared much more readily in comparison to outward direction. It also has interesting feature of displaying a variable conductance, where the conductance positively correlates with the extracellular potassium concentration, which means that higher the potassium concentration outside the cell, higher the conductance through these channels. Kir channels are categorized into seven major subfamilies, Kir1 to Kir7. Kir channels have different gating mechanisms as well. Kir3 and Kir6 are primarily activated by intracellular G-protein subunit. Because it has relatively low open probability compared to rest of its families, it has little impact on potassium buffering. Kir1 and Kir7 are mainly expressed in epithelia cells, such as those in kidney, choroid plexus, or retinal pigment epithelium and have no impact on spatial buffering. Kir2 however are expressed in brain and glial cell population. Kir4 and Kir5 are, along with Kir2 are located in Muller cells and have important role in potassium siphoning. There are some discrepancies among studies on expression of these channels in stated locations. Kir channels aren’t the only channels responsible for spatial buffering. There is also a potassium channel with strange distribution of 6% of the conductance being in the outer cell while 94% being in the endfoot.

Potassium siphoning

Potassium spatial buffering that occurs in retinas, where the muller cell is the principal glial cell type, is called potassium siphoning.

History

First support of potassium spatial buffering was supported by classic work by Orkand et al, where amphibians, when the optic nevers were stimulated, lead to slow deplolarization and repolarization in glial cells surrounding the nonmyelinated axons.

Diseases

In patients with Tuberous Sclerosis Complex (TSC), abnormalities occur in astrocyte, which leads to pathogenesis of neurological dysfunction in this disease. TSC is a multisystem genetic disease with mutation in either TSC1 or TSC2 gene. It results in disabling neurological symptoms such as mental retardation, autism, and seizures. Glial cells have important physiological roles of regulating neuronal excitability and preventing epilepsy. Astrocytes maintain homeostasis of excitatory substances, such as extracellular potassium, by immediate uptake through specific potassium channels and sodium potassium pumps. It is also regulated by potassium spatial buffering via astrocyte networks where astrocytes are coupled through gap junctions. Mutations in TSC1 or TSC2 gene often results in decreased expression of the astrocytic connexin protein, Cx43. With impairment in gap junction coupling between astrocytes, myriad of abnormalities in potassium buffering occurs which results in increased extracellular potassium concentration and may predispose to neuronal hyperexcitability and seizures.

Demyelinating Diseases of the central nervous system, such as Neuromyelitis Optica, often leads to molecular components of the panglial syncytium being compromised, which leads to blocking of potassium spatial buffering. Without mechanism of potassium buffering, potassium induced osmotic swelling of myelin occurs where myelins are destroyed and axonal salutatory conduction ceases.