Introduction

The Na+ K+ pump is an electrogenic transmembrane ATPase first discovered in 1957 and situated in the outer plasma membrane of the cells; on the cytosolic side.[1][2] The Na+ K+ ATPase pumps 3 Na+ out of the cell and 2K+ that into the cell, for every single ATP consumed. The plasma membrane is a lipid bilayer that arranged asymmetrically, containing cholesterol, phospholipids, glycolipids, sphingolipid, and proteins within the membrane.[3][4] The Na+K+-ATPase pump helps to maintain osmotic equilibrium and membrane potential in cells.

The sodium and potassium move against the concentration gradients. The Na+ K+-ATPase pump maintains the gradient of a higher concentration of sodium extracellularly and a higher level of potassium intracellularly. The sustained concentration gradient is crucial for physiological processes in many organs and has an ongoing role in stabilizing the resting membrane potential of the cell, regulation of the cell volume and in the cell signal transduction.[2] It plays a crucial role on other physiological processes, such as maintenance of filtering waste products in the nephrons (kidneys), sperm motility, and production of the neuronal action potential.[5] Furthermore, the physiologic consequences of inhibiting the Na+-K+ ATPase are useful and the target in many pharmacologic applications. 

Na, K-ATPase is a crucial scaffolding protein that can interact with signaling proteins such as protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K).[6]

Cellular

Structurally, the Na+ K+ ATPase is composed of a catalytic alpha subunit and an auxiliary beta subunit.[7] Some Na-K ATPases include a subunit that is tissue-specific and belongs to the FXYD protein family.[8] The alpha subunit contains a transmembrane region which is composed of 10 helices, referred to as MA1-M10. Within these ten helices, ion binding sites, specifically three binding sites that bind to Na+ in the E1 state and two binding sites that bind to K+ in the E2 state.[9][10][11][12] The structure of the Na-K ATPase is composed of three sites. Site one and two overlaps within both the E1 and E2 state. However, site three is exclusively in the E1 state and is between the M5, M6, and M8 transmembrane helices, which bind to Na+ and catalyze H+ transport as well,[13][14] dependent on the Na+, K+, and H+ concentrations.[15] According to previous studies, the pump’s E2 state selectivity for K+ may be due to ion binding pocket protonation.[16]

Function

Sodium and potassium gradients function in various organ systems' physiologic processes.[5] The kidneys have a high level of expression of the Na, K-ATPase, with the distal convoluted tubule expressing up to 50 million pumps per cell. This sodium gradient is necessary for the kidney to filter waste products in the blood, reabsorb amino acids, reabsorb glucose, regulate electrolyte levels in the blood, and to maintain pH.[17]

Sperm cells also use the Na, K-ATPase, but they use a different isoform necessary for preserving fertility in males. Sperm needs the Na, K ATPase to regulate membrane potential and ions, which is necessary for sperm motility and the sperm’s acrosome functioning during penetration into the egg.[18]

The brain also requires NA, K ATPase activity. Neurons need the Na, K ATPase pump to reverse postsynaptic sodium flux to re-establish the potassium and sodium gradients which are necessary to fire action potentials. Astrocytes also need Na, K ATPase pump to maintain the sodium gradient as the sodium gradient maintains neurotransmitter reuptake. Na, K ATPases in the gray matter consumes a significant amount of energy, up to three-quarters of energy is absorbed by Na, K ATPases in the gray matter while merely a quarter of the total energy gets utilized for protein synthesis and molecular synthesis.[19]

Pathophysiology

The Na+-K+ ATPase plays a prominent role in thyroid pathophysiology. In hyperparathyroidism, there is an increase in heat intolerance, increased sweating, and increased weight loss due to the increased synthesis of Na+-K+ ATPase induced by the excessive thyroid hormone. This increased synthesis of Na+-K+ ATPase then increases basal metabolic rate, which then increases oxygen consumption, respiratory rate, body temperature, and calorigenesis.[20]

Clinical Significance

As the Na+-K+ ATPase is essential for maintaining various cellular functions, its inhibition could result in diverse pathologic states. Studies show that patients with heart failure have a 40% lower concentration of total Na, K-ATPase.[21] One significant clinical application is in cardiovascular pharmacology. For example, ouabain is a cardiac glycoside which inhibits the Na+-K+ ATPase by binding to the K+ site. Other cardiac glycosides such as digoxin and digitoxin directly inhibit the Na+-K+ ATPase.[22] This inhibition causes a buildup of excessive K+ extracellularly, and accumulation of excessive Na+ intracellularly as the Na+-K+ ATPase can no longer pump K+ into the cell or pump Na+ out of the cell. This buildup of intracellular Na+ hinders the concentration gradient that usually drives the Na+/Ca 2+ channel exchanger, which generally pumps Na+ into the cell and Ca 2+ out of the cell because the concentration gradient is not favorable for Na+ to enter the cell as excessive Na+ has built up intracellularly. This indirect inhibition of Na+/Ca 2+ exchange, therefore, causes a buildup of Ca 2+ intracellularly because the exchanger cannot allow Ca 2+ to exit the cell since it cannot accept Na+ into the cell. This increased intracellular Ca 2+ then increases cardiac contractility. This positive inotropy stimulates the vagus nerve, causing a decrease in heart rate. This physiology is clinically significant in the treatment of heart failure as it increases contractility of the heart. It is also clinically significant in the treatment of atrial fibrillation as it decreases conduction of the atrioventricular node and causes depression of the sinoatrial node.[23] Diuretic therapy has also been shown to reduce myocardial Na, K-ATPase when there is potassium loss. In contrast, angiotensin-converting enzyme inhibitors could stimulate the activity of the Na, K pump.[21]

Another significant clinical application includes the effect of beta-adrenergic agonists in increasing the number of Na+/K+ ATPase channels; this is because beta-adrenergic agonists can enhance the gene expression of the Na+-K+-ATPase pump, which ultimately results in an increased quantity of the enzyme and therefore increased the activity of the enzyme. Because of this increased quantity of Na+/K+ ATPase, more potassium is pumped into the cell, causing a buildup of intracellular potassium. Therefore, extracellularly, this inward shift of potassium results in hypokalemia in the extracellular blood. Thus beta-adrenergic agonists can cause increased Na+ transport out of the cell as well. Increased Na+ transport extracellularly across alveolar epithelial cells for example, which would then cause lung liquid to follow this flow of Na+, ultimately stimulating lung liquid clearance.[24]]

Insulin also causes clinically significant effects on the Na+/K+ ATPase. Insulin increases the number of Na+/K+ ATPase pumps in the membrane as well, this leads to an intracellular shift of potassium, causing hypokalemia in the extracellular space of the blood.[25]

There are reports of abnormal expression levels, or activity of the Na+K+ pump in diabetes, hypertension, Alzheimer disease, and in various tumors including glioblastoma, non-small cell lung carcinoma, breast cancer, melanoma, colorectal carcinoma, and bladder cancer.[26].

Na+ K+-ATPase and its endogenous regulators, the endogenous cardiac steroids (ECS), play a role in the in the etiology of bipolar disorder and is a potential target for drug development for the treatment.[27]

 Both RNA and DNA viruses can directly affect Na, K-ATPase function, in particular, viral infections targeting the host cell components. Na, K-ATPase holds promise as an antiviral strategy to minimize the resistance to antiviral drugs and has been shown to be effective.[28] Cardiac glycosides inhibit cytomegalovirus (CMV) replication, with an additive effect when combined with antiviral drugs such as ganciclovir.[29] Cardiac glycosides can also be active on other DNA viruses such as herpes simplex virus (HSV) by inhibiting the expression of a viral gene.[30]

There is evidence of a Na/K-ATPase oxidant amplification loop in the process of aging, obesity, and cardiovascular disease.[31]