Expression of Kir4.1 and Kir5.1 inwardly rectifying potassium channels in oligodendrocytes, the myelinating cells of the CNS

Abstract

The inwardly rectifying K+ channel subtype Kir5.1 is only functional as a heteromeric channel with Kir4.1. In the CNS, Kir4.1 is localised to astrocytes and is the molecular basis of their strongly negative membrane potential. Oligodendrocytes are the specialised myelinating glia of the CNS and their resting membrane potential provides the driving force for ion and water transport that is essential for myelination. However, little is known about the ion channel profile of mature myelinating oligodendrocytes. Here, we identify for the first time colocalization of Kir5.1 with Kir4.1 in oligodendrocytes in white matter. Immunolocalization with membrane-bound Na+/K+-ATPase and western blot of the plasma membrane fraction of the optic nerve, a typical CNS white matter tract containing axons and the oligodendrocytes that myelinate them, demonstrates that Kir4.1 and Kir5.1 are colocalized on oligodendrocyte cell membranes. Co-immunoprecipitation provides evidence that oligodendrocytes and astrocytes express a combination of homomeric Kir4.1 and heteromeric Kir4.1/Kir5.1 channels. Genetic knock-out and shRNA to ablate Kir4.1 indicates plasmalemmal expression of Kir5.1 in glia is largely dependent on Kir4.1 and the plasmalemmal anchoring protein PSD-95. The results demonstrate that, in addition to astrocytes, oligodendrocytes express both homomeric Kir4.1 and heteromeric Kir4.1/Kir5.1 channels. In astrocytes, these channels are essential to their key functions of K+ uptake and CO2/H+ chemosensation. We propose Kir4.1/Kir5.1 channels have equivalent functions in oligodendrocytes, maintaining myelin integrity in the face of large ionic shifts associated with action potential propagation along myelinated axons.

Genetic mutation of Kcnj16 identifies Kir5.1‐containing channels as key regulators of acute and chronic pH homeostasis

“…This is an intriguing result given that Kir5.1‐containing Kir channels have not been implicated in hypoxia‐sensing mechanisms within the glomus cells of the carotid bodies or the recently proposed astrocyte‐mediated hypoxia‐sensing mechanisms in the brain (31–33). However, Kir5.1 expression has been detected in the carotid bodies (34) and brainstem astrocytes and glia (6,9), and both have known pH sensitivity (10, 35). Despite the loss of the hypoxic ventilatory response in SS Kcnj16−/− rats, it is possible that the chronic metabolic acidosis leads to hyperventilation at rest through a carotid body‐mediated mechanism given that the blood–brain barrier protects the brain to a large extent during systemic metabolic acidosis (36).…”

“…Among other genes we identified was Kcnj16 , which encodes the inwardly rectifying K + (Kir) 5.1 channel. The Kir5.1 subunit is thought to primarily form heterotetrameric channels with other Kir family members, particularly with Kir4.1 and Kir2.1 channels (9,10). Atypically, they may function independently as a homomeric Kir5.1 channel (11).…”

“…Heterotetrameric Kir channels pass K + currents that contribute to resting membrane potential, and those containing Kir5.1 subunits are inhibited as pH drops within a physiologic range (3, 12, 13). Kir2.1, Kir4.1, and Kir5.1 channels are highly expressed in astrocytes, oligodendrocytes, and select neurons in the brain (6,9,14). These channels are also highly expressed in epithelial cells in the distal nephron (15, 16), where they modulate membrane potential in a pH‐dependent manner and participate in K + recycling, Na + and Cl − resorption, and acid secretion (17).…”

Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia

“…There are 92 human genes encoding different potassium channels [HUGO Gene Nomenclature Committee (HGNC) Database, www.genenames.org]. Some of these channels such as KCNJ10 and KCNJ16 are restricted to oligodendrocytes where they maintain the resting potential of oligodendrocytes necessary for myelin integrity (Brasko et al 2016). Given the neurophysiological roles of potassium channels, genetic variance in potassium channel genes may have a shared common effect on the function of myelinated axons and processing speed.…”

Potassium channel dysfunction in neurons and astrocytes in Huntington's disease

“…NG2‐glia and oligodendrocytes constitute two major populations of macroglia in the CNS and they are fundamental to neurons' myelin production and formation . A recent study clearly showed K + channel mRNA and protein functional expression in both cell types . It thus becomes necessary and relevant to elucidate a potential interaction of K + channels with myelin‐related genes.…”