Requirement of Glycogenolysis for Uptake of Increased Extracellular K+ in Astrocytes: Potential Implications for K+ Homeostasis and Glycogen Usage in Brain

Abstract

The importance of astrocytic K(+) uptake for extracellular K(+) ([K(+)](e)) clearance during neuronal stimulation or pathophysiological conditions is increasingly acknowledged. It occurs by preferential stimulation of the astrocytic Na(+),K(+)-ATPase, which has higher K(m) and V(max) values than its neuronal counterpart, at more highly increased [K(+)](e) with additional support of the cotransporter NKCC1. Triggered by a recent DiNuzzo et al. paper, we used administration of the glycogenolysis inhibitor DAB to primary cultures of mouse astrocytes to determine whether K(+) uptake required K(+)-stimulated glycogenolysis. KCl was increased by either 5 mM (stimulating only the Na(+),K(+)-ATPase) or 10 mM (stimulating both transporters) in glucose-containing saline media prepared to become iso-osmotic after the addition. DAB completely inhibited both uptakes, the Na(+),K(+)-ATPase-mediated by preventing Na(+) uptake for stimulation of its intracellular Na(+)-activated site, and the NKCC1-mediated uptake by inhibition of depolarization- and L-channel-mediated Ca(2+) uptake. Drugs inhibiting the signaling pathways involved in either of these processes also abolished K(+) uptake. Assuming similar in vivo characteristics, partly supported by literature data, K(+)-stimulated astrocytic K(+) uptake must discontinue after normalization of extracellular K(+). This will allow Kir1.4-mediated release and reuptake by the less powerful neuronal Na(+),K(+)-ATPase.

A Subconvulsive Dose of Kainate Selectively Compromises Astrocytic Metabolism in the Mouse Brain In Vivo

“…36 Glycogen was suggested to be essential for maintenance of the homeostasis of extracellular depolarizing agents such as glutamate and K þ as previously demonstrated. 37,38 Similarly, glycogen may be involved in the regulation and possibly restriction of neuronal activity when mice are injected with kainate that also involves an elevated extracellular K þ concentration. It should be noted, however, that although glycogen is confined to astrocytes, 39 it is also able to sustain energy homeostasis in neurons via conversion to lactate and transfer to the neuronal compartment for reconversion to pyruvate entering the TCA cycle for energy production.…”

Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine

“…This may be important for behavioural effects of SSRIs. Glycogen turnover, i.e., interspersed glycogen synthesis and glycogenolysis, is indispensable during learning Hertz et al 2013). The acute memory-enhancing, glycogenolysis-dependent effect of both fluoxetine and paroxetine has been mentioned (O'Dowd et al 1994;1995;Gibbs and Hertz 2014;Suzuki et al 2011;Gibbs and Hertz 2014;Gao et al 2016).…”

“…Glycogen turnover, i.e., interspersed glycogen synthesis and glycogenolysis, is indispensable for learning Hertz et al 2013). The acute memory-enhancing, as well as glycogenolysis-dependent effect of both fluoxetine and paroxetine has been also described (Gibbs and Hertz 2014).…”

Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity

“…a From Jayakumar et al [142] and b from Jayakumar et al [143] increased when neuronal excitation raises extracellular K + , except as a consequence of glutamate uptake [171]. Experiments in cultured astrocytes known to mimic other signaling events and gene expression in astrocytes in situ [172] have shown that signaling mediated by nanomolar concentrations of ouabain opens an astrocytic Na + channel and thereby enables K + -stimulated K + uptake in astrocytes [146,169,173]. This effect is probably essential for an initial Na + ,K + -ATPase-mediated K + uptake in astrocytes during clearance of elevated extracellular K + following neuronal activity, at least in astrocytes that have not accumulated Na + during glutamate uptake.…”