It's All about Timing: The Involvement of Kir4.1 Channel Regulation in Acute Ischemic Stroke Pathology

Abstract

An acute ischemic stroke is characterized by the presence of a blood clot that limits blood flow to the brain resulting in subsequent neuronal loss. Acute stroke threatens neuronal survival, which relies heavily upon proper function of astrocytes. Neurons are more susceptible to cell death when an astrocyte is unable to carry out its normal functions in supporting the neuron in the area affected by the stroke (Rossi et al., 2007; Takano et al., 2009). For example, under normal conditions, astrocytes initially swell in response to changes in extracellular osmotic pressure and then reduce their regulatory volume in response to volume-activated potassium (K+) and chloride channels (Vella et al., 2015). This astroglial swelling may be overwhelmed, under ischemic conditions, due to the increased levels of glutamate and extracellular K+ (Lai et al., 2014; Vella et al., 2015). The increase in extracellular K+ contributes to neuronal damage and loss through the initiation of harmful secondary cascades (Nwaobi et al., 2016). Reducing the amount of extracellular K+ could, in theory, limit or prevent neuronal damage and loss resulting in an improved prognosis for individuals following ischemic stroke. Kir4.1, an inwardly rectifying K+ channel, has demonstrated an ability to regulate the rapid reuptake of this ion to return the cell to basal levels allowing it to fire again in rapid transmission (Sibille et al., 2015). Despite growing interest in this area, the underlying mechanism suggesting that neuroprotection could occur through modification of the Kir4.1 channel's activity has yet to be described. The purpose of this review is to examine the current literature and propose potential underlying mechanisms involving Kir4.1, specially the mammalian target of rapamycin (mTOR) and/or autophagic pathways, in the pathogenesis of ischemic stroke. The hope is that this review will instigate further investigation of Kir4.1 as a modulator of stroke pathology.

Dysregulation of Astrocyte Ion Homeostasis and Its Relevance for Stroke-Induced Brain Damage

“…There is a wealth of data and investigations demonstrating that energy restriction and accompanying spreading depolarization events are accompanied by a failure of extracellular K + -homeostasis in which astrocytes are critically involved [ 134 , 150 , 151 , 152 ]. A recent study also proposed an involvement of microglia in extracellular K + -homeostasis during spreading depolarisations [ 153 ].…”

A Purinergic P2 Receptor Family-Mediated Increase in Thrombospondin-1 Bolsters Synaptic Density and Epileptic Seizure Activity in the Amygdala-Kindling Rat Model

“…In recent years, astrocytes have been found to function not only as neuronal support cells and neuroimmune cells but also as regulators that stabilize synapses (Codazzi et al, 2015 ; Murphy-Royal et al, 2015 ; Charvériat et al, 2017 ; van Deijk et al, 2017 ; Dubový et al, 2018 ; Milton and Smith, 2018 ). Barres and Smith ( 2001 ) found that including astrocytes in neuronal cultures, even as a feeder lay, can significantly increase synapse formation, and these synapses demonstrated normal postsynaptic potentials and frequency multiplication (Ullian et al, 2001 ).…”

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

“…The resultant increase of glutamate in the synaptic cleft resulting from K ir 4.1 inhibition results in abnormal modulation of synaptic transmission and network level communication [277,281] and is associated with the development and maintenance of neuroinflammation [282,283]. The pathological significance of K ir 4.1 downregulation in a neuroinflammatory environment is further emphasized by the results of several in vivo studies reporting reduced expression and/or function of this receptor in several neurodegenerative diseases, most notably multiple sclerosis and AD [284][285][286][287].…”

“…Hence, improvements in glutamate reuptake by astrocytes coupled with amelioration of glutamate dyshomeostasis, which may stem from nutritional ketosis would be expected to produce concomitant improvements in K ir 4.1-mediated astrocyte K + buffering. Increased levels of ATP fostered by the bioenergetic and metabolic consequences of induced ketosis may also be of therapeutic benefit as far as improving K + homeostasis mediated by K ir 4.1 is concerned as the optimum function of this receptor is also dependent on adequate levels of ATP [285,286,295,296]. Consequently, the documented improvements in oxidative stress, neuroinflammation, glutamate homeostasis, and ATP production in the CNS following prolonged ingestion of various KDs would be expected to result in beneficial effects on K ir 4.1 levels and function.…”