Introduction

There are 2 main modes of transport of molecules across any biological membrane. These are passive and active transport. Passive transport, most commonly by diffusion, occurs along a high-to-low concentration gradient. No energy is necessary for this mode of transport. Examples will include the diffusion of gases across alveolar membranes and the diffusion of neurotransmitters such as acetylcholine across the synapse or neuromuscular junction. Osmosis is a form of passive transport when water molecules move from low solute concentration(high water concentration) to high solute or low water concentration across a membrane that is not permeable to the solute. There is a form of passive transport called facilitated diffusion. It occurs when molecules such as glucose or amino acids move from high concentration to low concentration facilitated by carrier proteins or pores in the membrane. Active transport requires energy for the process by transporting molecules against a concentration or electrochemical gradient.

Active transport is an energy-driven process where membrane proteins transport molecules across cells, mainly classified as primary or secondary, based on how energy is coupled to fuel these mechanisms. The former constitutes the means by which a chemical reaction, e.g., ATP hydrolysis, powers the direct transport of molecules to establish specific concentration gradients, as seen with sodium/potassium-ATPase and hydrogen-ATPase pumps. The latter employs those established gradients to transport other molecules.[1][2] These gradients support the roles of other membrane proteins and other workings of the cell and are crucial to maintaining cellular and bodily homeostasis. As such, the importance of active transport is apparent when considering the various defects throughout the body that can manifest in a wide variety of diseases, including cystic fibrosis and cholera, all because of an impairment in some aspect of active transport.[3]

Cellular Level

Transmembrane proteins are necessary to transport certain substances across cell membranes because the phospholipid bilayer or electrochemical gradient would otherwise impede their movement. Active transport is one manner by which cells accomplish this movement by acting against the formation of an equilibrium, typically by concentrating molecules depending on the various needs of the cell, e.g., ions, sugars, and amino acids. Primary/direct active transport predominantly employs transmembrane ATPases and commonly transports metal ions like sodium, potassium, magnesium, and calcium through ion pumps/channels. Secondary active (coupled) transport capitalizes on the energy stored in electrochemical gradients established via direct active transport, predominantly created by sodium ions via the sodium-potassium ATPase, to move other molecules against their respective gradients, notably without directly coupling to ATP.[2]

Function

Active transport requires energy (ATP) since it takes molecules from a lower to a higher concentration, ie, against its concentration or electrochemical gradient. Importantly, active transport is necessary for the homeostasis of ions and molecules, and a significant portion of the available energy goes toward maintaining these processes. In particular, the sodium-potassium pump is required to maintain cell potentials and can be seen in neuronal action potentials.[4] Secondary action potentials can be seen inside the electron transport chain, where a hydrogen electrochemical gradient is established to synthesize ATP. An example of an antiporter is the sodium-calcium antiporter that exists in myocytes to maintain a low intracellular calcium concentration, and an example of a symporter is the sodium-dependent glucose cotransporter that transporter that transports glucose/galactose with 2 sodium ions into the cell.[5][6]

Mechanism

An example of primary (carrier-mediated) active transport, the sodium-potassium pump directly utilizes ATP to bring 3 sodium ions out of cells and 2 potassium ions into them via a cycle of changes to the shape of the protein pump, ie:

1. The protein is initially open to the cell interior, allowing sodium ions to adhere to the high-affinity pump.
2. Binding of sodium induces the phosphorylation of the pump via ATP hydrolysis.
3. This chemical modification to the pump causes it to undergo a conformational change so that it is instead open to the cell exterior. In this new conformation, the pump now has a low affinity towards sodium, causing those ions to get released into the extracellular space.
4. The shape change also creates a high-affinity environment for potassium ions on the pump, so potassium ions can thus bind, causing the release of the attached phosphate group.
5. Removal of that phosphate group returns the pump to its starting conformation, ie, facing the cell's inside.
6. Again, the pump reverses its affinity from potassium to sodium, so the potassium ions detach as the sodium ions did on the outside. Now, the pump can bind to sodium as before and repeat the process.[7][8]

The establishment of an electrochemical gradient following this process mainly occurs via potassium efflux channels that allow the diffusion of potassium along its concentration gradient. Such electrochemical gradients can then serve to power secondary active transport. Secondary active transport employs cotransporters to transport multiple solutes, and they can be divided based on whether the transporters used are symporters or antiporters, ie, transporting solutes in the same or different directions. The antiporter utilizes the energetically favorable movement of one solute down its gradient to allow the otherwise energetically unfavorable movement of another solute against its gradient. The sodium-calcium exchanger, for example, transports 3 sodium ions into the cell in exchange for one calcium out, accomplished because of the previously established sodium concentration gradient.[5] Like the antiporter, the symporter capitalizes on the movement of a solute down its gradient to facilitate the uphill movement of another solute against its gradient, but both move towards the same location.[6] 

Pathophysiology

As active transport is an integral process for cells throughout the body, a wide plethora of diseases have a component of abnormal active transport, often in the form of a mutation that impairs or augments function.

Type I (distal) renal tubular acidosis (RTA) is a prime example of impaired active transport, whereby hydrogen ions are unable to be secreted into the urine from the kidney's alpha-intercalated cells (which contain hydrogen ion ATPases and hydrogen-potassium ATPases).[11] Due to increased urinary alkalinity, distal RTA increases the likelihood of developing kidney stones.[9] The impaired function of active transport of hydrogen ions in the intercalated cells of the collecting tubules is responsible for all the known genetic causes of distal renal tubular acidosis.

Another renal tubular defect is Bartter syndrome, an autosomal recessive reabsorption defect in the sodium-potassium-chloride-chloride (NKCC) cotransporter in the kidneys, ultimately leading to hypokalemia and metabolic alkalosis. Typically, the NKCC protein utilizes the movement of sodium along its concentration gradient (established by a sodium-potassium ATPase on the other side) to cotransport potassium and chloride, so this defect prevents the reabsorption of all these 3 ions.

Cystic fibrosis (CF) is an autosomal recessive disorder common among Caucasians, whereby CFTR (Cystic Fibrosis Conductance Regulator gene), which normally encodes for an ATP-gated chloride channel, is mutated, causing the protein to misfold and not be transported to the cell membrane to perform its functions. The CFTR protein allows chloride to move out of cells, with sodium and water molecules following. This movement of water out of cells hydrates the mucosal surface and thins the secretions so they can get cleared from the tubular structures such as bronchial passage and secretary ducts. In cystic fibrosis, the dehydrated mucosal surface with little chloride and water will lead to thick mucus, which allows bacteria to grow and digestive enzymes to move along the pancreatic ducts. As a result, there are recurrent pulmonary infections, pancreatic insufficiency, malabsorption, and steatorrhea.[10][11] The diagnosis of CF is with an increased chloride concentration in a pilocarpine-induced sweat test.[12]

Also indirectly stimulating the CFTR channel is the cholera toxin, commonly consumed from contaminated water or uncooked food, which drastically decreases absorption in the intestinal lumen, resulting in voluminous watery diarrhea.[13][3]

Clinical Significance

A highly illustrative example of the importance of active transport is the use of cardiac glycosides like digoxin, which inhibit sodium-potassium ATPase in cardiac cells. Employing primary active transport, this protein normally acts to extrude sodium out of myocytes in exchange for potassium into the cells. In the presence of cardiac glycoside, the intracellular sodium will be higher. This indirectly inhibits the sodium-calcium exchanger, which normally brings sodium into the cell in exchange for calcium leaving. As such, more calcium is unable to leave the cell, so more calcium can act intracellularly to stimulate cardiac contractility or positive inotropy, implicating its usage in diseases that have decreased inotropy like heart failure. Because potassium is kept in the extracellular space, it can build up and cause hyperkalemia.[14][15] 

The above-mentioned renal tubular defects, like Bartter syndrome, share cellular mechanisms similar to many diuretics, which may target the same channels. Similar to Bartter syndrome, loop diuretics also block the sodium-potassium-chloride-chloride channels of the kidneys, preventing reabsorption of salts and the water that follows along with it to aid in treating edema and hypertension. Thiazide diuretics similarly work by blocking the kidney's sodium-chloride channels.

Active transport may also be necessary for the effectiveness of certain drugs. Aminoglycosides get transported into cells via oxygen-dependent active transport, so they cannot work on anaerobic bacteria.[14]