Regulation of Neuronal Na⁺/K⁺-ATPase by Specific Protein Kinases and Protein Phosphatases

Abstract

The Na ϩ /K ϩ -ATPase (NKA) is a ubiquitous membrane-bound enzyme responsible for generating and maintaining the Na ϩ and K ϩ electrochemical gradients across the plasmalemma of living cells. Numerous studies in non-neuronal tissues have shown that this transport mechanism is reversibly regulated by phosphorylation/dephosphorylation of the catalytic ␣ subunit and/or associated proteins. In neurons, Na ϩ /K ϩ transport by NKA is essential for almost all neuronal operations, consuming up to two-thirds of the neuron's energy expenditure. However, little is known about its cellular regulatory mechanisms. Here we have used an electrophysiological approach to monitor NKA transport activity in male rat hippocampal neurons in situ. We report that this activity is regulated by a balance between serine/threonine phosphorylation and dephosphorylation. Phosphorylation by the protein kinases PKG and PKC inhibits NKA activity, whereas dephosphorylation by the protein phosphatases PP-1 and PP-2B (calcineurin) reverses this effect. Given that these kinases and phosphatases serve as downstream effectors in key neuronal signaling pathways, they may mediate the coupling of primary messengers, such as neurotransmitters, hormones, and growth factors, to the NKAs, through which multiple brain functions can be regulated or dysregulated.

Molecular mechanisms of Na,K-ATPase dysregulation driving alveolar epithelial barrier failure in severe COVID-19

“…Apart from the pulmonary alveolar epithelium, several other cell types of various tissues and organs utilize the Na þ gradient generated by the Na,K-ATPase to maintain their functions. For instance, the Na,K-ATPase plays an important role in heart muscle metabolism, endothelial and vascular function, regulating neurotransmitter reuptake in neurons, reabsorption of amino acids and glucose in kidneys, regulation of electrolyte balance, and maintaining blood pH and pressure (11,(25)(26)(27). It is now well established that patients with a SARS-CoV-2 infection and certain comorbidities, such as chronic lung disease, hypertension, diabetes, obesity, and chronic kidney disease have worse outcomes (28).…”

Afterhyperpolarization amplitude in CA1 pyramidal cells of aged Long-Evans rats characterized for individual differences

“…This pump is electrogenic such that an increase on its activity, after a burst of APs for example, produces an outward current that results in a detectable after hyperpolarization (Gulledge et al, 2013). In turn, the pump activity is regulated by multiple signaling pathways (de Lores Arnaiz and Ordieres, 2014) via protein kinases and protein phosphatases (Mohan et al, 2019) . In this context, it is important to note that transmembrane ion gradients can be severely disrupted during the preparation of slices.…”

Nephroprotective Property of C. chayamansa Aqueous Leaf Extract in Diabetic Rats

“…The dysregulation of chief electrolytes especially Na + , K + and Ca 2+ have been reported to be the characteristic feature in the renal and cardiovascular diseases [34]. Most of the studies in literatures indicate that elevation of intracellular Na + and increase in K + ions was associated with a reduced activity of erythrocyte Na+-K+-ATPase pump [35]. Inhibition of Na+-K+-ATPase enzyme activity is said to be the main factor as in most of the kidney and cardiovascular diseases, inhibited or reduced ATPase activity has been observed.…”