Inwardly rectifying potassium channels (Kir) in central nervous system glia: a special role for Kir4.1 in glial functions

Abstract

A high selective membrane permeability to potassium ions (K + ) and a strongly negative resting membrane potential (RMP) are considered fundamental properties of glial cells [1,2]. Glia express a wide range of K + channels, but inwardly rectifying K + channels (Kir) are predominantly responsible for the high K + permeabili- AbstractGlia in the central nervous system (CNS) express diverse inward rectifying potassium channels (Kir). The major function of Kir is in establishing the high potassium (K + ) selectivity of the glial cell membrane and strongly negative resting membrane potential (RMP), which are characteristic physiological properties of glia. The classical property of Kir is that K + flows inwards when the RMP is negative to the equilibrium potential for K + (E K ), but at more positive potentials outward currents are inhibited. This provides the driving force for glial uptake of K + released during neuronal activity, by the processes of "K + spatial buffering" and "K + siphoning", considered a key function of astrocytes, the main glial cell type in the CNS. Glia express multiple Kir channel subtypes, which are likely to have distinct functional roles related to their differences in conductance, and sensitivity to intracellular and extracellular factors, including pH, ATP, G-proteins, neurotransmitters and hormones. A feature of CNS glia is their specific expression of the Kir4.1 subtype, which is a major K + conductance in glial cell membranes and has a key role in setting the glial RMP. It is proposed that Kir4.1 have a primary function in K + regulation, both as homomeric channels and as heteromeric channels by co-assembly with Kir5.1 and probably Kir2.0 subtypes. Significantly, Kir4.1 are also expressed by oligodendrocytes, the myelin-forming cells of the CNS, and the genetic ablation of Kir4.1 results in severe hypomyelination. Hence, Kir, and in particular Kir4.1, are key regulators of glial functions, which in turn determine neuronal excitability and axonal conduction.

Astrocyte dysfunction in temporal lobe epilepsy: K+ channels and gap junction coupling

“…In astrocytes, the inwardly rectifying K 1 channel, Kir4.1, which is regulated by intracellular adenosine triphosphate (ATP), is thought to allow for K 1 influx at negative membrane potentials (for review see Butt and Kalsi, 2006;Hibino et al, 2010;Olsen and Sontheimer, 2008). Genetic inactivation of the Kir4.1 encoding gene, KCNJ10, in animal models substantiated an outstanding role for Kir4.1 in glial K 1 buffering (Djukic et al, 2007;Kofuji et al, 2000).…”

Ion channels in autoimmune neurodegeneration

“…They affect the electrotonic conductance and repolarisation of the action potential generated at the node by mediating K + outward currents [60]. Glia cells also possess inwardly rectifying potassium channels (K ir 4.1) that support the potassium homeostasis in the extracellular space [7]. Demyelination induces alterations in K + channel expression and distribution, as there is an upregula- currents lead to an intracellular potassium depletion that is assumed to be a first step in apoptotic cascades as it triggers water loss and disinhibition of intracellular proapoptotic enzymes [61].…”

“…The regulation of the immune response is fundamentally dependent on ion channels which are expressed on immune cells and which allow peripheral T lymphocytes to proliferate and to produce inflammatory cytokines [5]. Ion channels on neurons and glia cells affect the mechanisms that induce axonal and neuronal degeneration in white matter of the brain and spinal cord [6,7]. The application of different sodium, potassium and calcium channel inhibitors considerably ameliorates the EAE disease course as well as clinical severity, and it postpones the disease onset after immunization in comparison to sham-treated control animals [5,8,9].…”

Characterization of Ionic Currents in Human Neural Stem Cells

“…However, HERG channels would typically be closed at holding potentials negative to 80 mV, and the activation kinetics and Ba 2+ sensitivity did not match well with the properties of hyperpolarization-activated nonselective cation currents. The family of inward rectifier K + channels is generally divided, on the basis of molecular and electrophysiological attributes, into seven subfamilies (Kir1.0∼ Kir7.0), which have more than 20 members (Doupnik et al, 1995;Nichols & Lopatin, 1997;Butt & Kalsi, 2006). We have not taken a molecular approach or a more detailed electrophysiological characterization of this hyperpolarizationactivated inward current.…”