P2C-Type ATPases and Their Regulation

Abstract

P2C-type ATPases are a subfamily of P-type ATPases comprising Na(+)/K(+)-ATPase and H(+)/K(+)-ATPase. Na(+)/K(+)-ATPase is ubiquitously expressed and has been implicated in several neurological diseases, whereas H(+)/K(+)-ATPase is found principally in the colon, stomach, and kidney. Both ATPases have two subunits, α and β, but Na(+)/K(+)-ATPase also has a regulatory subunit called FXYD, which has an important role in cancer. The most important functions of these ATPases are homeostasis, potassium regulation, and maintaining a gradient in different cell types, like epithelial cells. Na(+)/K(+)-ATPase has become a center of attention ever since it was proposed that it might play a crucial role in neurological disorders such as bipolar disorder, mania, depression, familial hemiplegic migraine, rapid-onset dystonia parkinsonism, chronic stress, epileptogenesis, and Alzheimer's disease. On the other hand, it has been reported that lithium could have a neuroprotective effect against ouabain, which is the best known Na(+)/K(+)-ATPase inhibitor, but and high concentrations of lithium could affect negatively H(+)/K(+)-ATPase activity, that has a key role in regulating acidosis and potassium deficiencies. Finally, potassium homeostasis regulation is composed of two main mechanisms, extrarenal and renal. Extrarenal mechanism controls plasma levels, shifting potassium from the extracellular to the intracellular, whereas renal mechanism concerns with body balance and is influenced by potassium intake and its urinary excretion. In this article, we discuss the functions, isoforms, and localization of P2C-type ATPases, describe some of their modulators, and discuss their implications in some diseases.

Cardiotonic Steroids as Modulators of Neuroinflammation

“…For many years, NKA has aroused the interest of many groups in studying not only its pumping function, structure, and biochemistry but also, more recently, its role in signal transduction ( 15 – 17 ). NKA is well known to be responsible for the maintenance of ionic homeostasis where the hydrolysis of one molecule of ATP allows the establishment of an electrochemical gradient through the cellular efflux of three Na + ions and an influx of two K + ions.…”

“…A further crucial role for the NKA is the re-establishment of the ionic gradient following neuronal action potential firing. This is due to the natural Na + and K + diffusion potential across the cell membrane, which establishes a steady state that is vital for all excitable tissues, and which needs to be repolarized after neuronal depolarization ( 15 , 18 ).…”

“…Interestingly, the distribution of the different isoforms varies according to cell type, tissue, stage of development, and species ( 19 – 21 ). The isoforms α1, α2, α3, and α4 have different expression profiles, with the α1 subunit being ubiquitously expressed and uniformly distributed, α2 being predominant in some specific cell types, including astrocytes and cardiac myocytes, α3 being more highly expressed in neurons and the ovaries, while α4 can be found only in spermatozoa ( 15 , 19 , 22 , 23 ). The NKA β-subunit seems to be a specific chaperone that is essential for both the traffic and correct plasma insertion site of newly synthesized α-subunits ( 24 ).…”

“…Furthermore, the β-subunit can even influence pump activity, given its modulation of K + affinity for the pump binding sites ( 25 , 26 ). Interestingly, β1 and β2 isoforms can both be found in the brain, with astrocytes expressing α1 and α2 in combination with β2, while neurons express α1 and α3 in combination with β1 or β2 ( 15 , 27 ).…”

P-type transport ATPases inLeishmaniaandTrypanosoma

“…However, the P 2C Na + /K + - and H + /K + -ATPases are heterodimers composed of a catalytic α-subunit and a ~40 kDa, glycosylated, regulatory β-subunit whose co-translational association with the α-subunit is absolutely required for protein maturation, membrane localization, stability and function of P 2C ATPases. The P 2C Na + /K + -ATPases can be further modified by a third subunit, the gamma or FXYD subunit, which affects substrate affinity and pump activity [132]. The P 4 -ATPase subfamily of aminophospholipid translocases also requires accessory β-subunit proteins for both correct trafficking to the membrane and lipid translocation activity [120].…”