Na(+), K(+)-ATPase: Ubiquitous Multifunctional Transmembrane Protein and its Relevance to Various Pathophysiological Conditions

The Na(+), K(+)-ATPase (NKA) is an ubiquitous enzyme consisting of α, β and γ subunits, and is responsible for the creation and maintenance of the Na(+) and K(+) gradients across the cell membrane by transporting 3 Na(+) out and 2 K(+) into the cell. Sodium pump regulation is tissue as well as isoform specific. Intracellular messengers differentially regulate the activity of the individual NKA isozymes. Regulation of specific NKA isozymes gives cells the ability to precisely coordinate NKA activity to their physiological requirements. It is the only known receptor for the cardiac glycosides used to treat congestive heart failure and cardiac arrhythmias. Endogenous ligands structurally similar to cardiac glycosides may act as natural regulators of the sodium pump in heart and other tissues. Identification of naturally occurring regulators of NKA could initiate the discovery of new hormone-like control systems involved in the etiology of selected disease processes, hence the importance of understanding the relation of the sodium pump and its ligands to disease. Diabetes has a marked effect on the metabolism of a variety of tissues and because the NKA is critical for the membrane potential and many transports, a change in its activity in diabetes would have profound consequence in these tissues. NKA is also involved in hypertension, salt balance, cardiovascular and renal disorders, sperm capacitation, cell volume regulation, apoptosis, rheumatoid arthritis, sepsis, neurological disorders, lung edema clearance and preeclampsia. NKA activity and expression in the collecting duct of kidney are modulated physiologically by hormones like aldosterone, vasopressin, and insulin. NKA enzyme activity and subunit levels are reduced in carcinoma, NKA-β levels were highly reduced in an invasive form of human renal clear cell carcinoma, androgen-dependent prostate cancer, in early stages of urothelial cancer, as well as in poorly differentiated, highly motile carcinoma cell lines obtained from various tissues suggesting a functional link between reduced NKA-β expression and cancer progression. It could be a target for the development of anticancer drugs as it serves as a signal transducer, it is a player in cell adhesion and its aberrant expression and activity are implicated in the development and progression of different cancers. KEYWORDS: Na(+), K(+)-ATPase (NKA); Cardiotonic steroids (CTS); Diabetes; Hypertension; Cardiovascular and renal disorders; Signal transducer; Anticancer drugs