Plasma membrane Ca2+ ATPase

Rendered image of the Ca²⁺ pump

The plasma membrane Ca²⁺ ATPase (PMCA) is a transport protein in the plasma membrane of cells that serves to remove calcium (Ca²⁺) from the cell. It is vital for regulating the amount of Ca²⁺ within cells. In fact, the PMCA is involved in removing Ca²⁺ from all eukaryotic cells. There is a very large transmembrane electrochemical gradient of Ca²⁺ driving the entry of the ion into cells, yet it is very important for cells to maintain low concentrations of Ca²⁺ for proper cell signalling; thus it is necessary for the cell to employ ion pumps to remove the Ca²⁺. The PMCA and the sodium calcium exchanger (NCX) are together the main regulators of intracellular Ca²⁺ concentrations. Since it transports Ca²⁺ into the extracellular space, the PMCA is also an important regulator of the calcium concentration in the extracellular space.

The PMCA belongs to a family of P-type primary ion transport ATPases that form an aspartyl phosphate intermediate.

The PMCA is expressed in a variety of tissues, including the brain.

Actions

The pump is powered by the hydrolysis of adenosine triphosphate (ATP), with a stoichiometry of two Ca²⁺ ions removed for each molecule of ATP hydrolysed. It binds tightly to Ca²⁺ ions (has a high affinity, with a K_m of 100 to 200 nM) but does not remove Ca²⁺ at a very fast rate. This is in contrast to the NCX, which has a low affinity and a high capacity. Thus the PMCA is effective at binding Ca²⁺ even when its concentrations within the cell are very low, so it is suited for maintaining Ca²⁺ at its normally very low levels. Calcium is an important second messenger, so its levels must be kept low in cells to prevent noise and keep signalling accurate. The NCX is better suited for removing large amounts of Ca²⁺ quickly, as is needed in neurons after an action potential. Thus the activities of the two types of pump complement each other.

The PMCA functions in a similar manner to other p-type ion pumps. ATP transfers a phosphate to the PMCA, which forms a phosphorylated intermediate.

Ca²⁺/calmodulin binds and further activates the PMCA, increasing the affinity of the protein's Ca²⁺ binding site 20 to 30 times. Calmodulin also increases the rate at which the pump extrudes Ca²⁺ from the cell, possibly up to ten fold.

In brain tissue, it has been postulated that certain types of PMCA are important for regulating synaptic activity, since the PMCA is involved in regulating the amount of calcium within the cell at the synapse, and Ca²⁺ is involved in release of synaptic vesicles.

Structure

The structure of the PMCA is similar to that of the SERCA calcium pumps which are responsible for removing calcium from the sarcoplasmic reticulum. It is thought that the PMCA pump has 10 segments that cross the plasma membrane, with both C and N termini on the inside of the cell. At the C terminus, there is a long "tail" of between 70 and 200 amino acids in length. This tail is thought to be responsible for regulation of the pump.

Isoforms

There are four isoforms of PMCA, called PMCA 1 through 4.

• ATP2B1 - PMCA1
• ATP2B2 - PMCA2
• ATP2B3 - PMCA3
• ATP2B4 - PMCA4

Each isoform is coded by a different gene and is expressed in different areas of the body. Alternate splicing of the mRNA transcripts of these genes results in different subtypes of these isoforms. Over 20 splice variants have been identified so far.

Three PMCA isoforms, PMCA1, PMCA2, and PMCA3, occur in the brain in varying distributions. PMCA1 is ubiquitous throughout all tissues in humans, and without it embryos do not survive. Lack of PMCA4, which is also very common in many tissues, is survivable, but leads to infertility in males. PMCA types 2 and 3 have a faster rate of extruding Ca²⁺ and are therefore better suited to excitable cell types such as those in nervous and muscle tissue, which experiences large influxes of Ca²⁺ when excited. PMCA types 1, 2, and 4 have been found in glial cells called astrocytes in mammals, though it was previously thought that only the NCX was present in glia. Astrocytes help to maintain ionic balance in the extracellular space in the brain.

Knock-out of PMCA2 causes inner ear problems, including hearing loss and problems with balance.

PMCA4 exists in caveolae. Isoform PMCA4b interacts with nitric oxide synthase and reduces synthesis of nitric oxide by that enzyme.

PMCA isoforms 1, 2 and 4 probably weigh about 153 kDa each.

Pathology

When the PMCA fails to function properly, disease can result. Improperly functioning PMCA proteins have been found associated with conditions such as sensorineural deafness, diabetes, and hypertension.

In excitotoxicity, a process in which excessive amounts of the neurotransmitter glutamate overactivate neurons, resulting in excessive influx of Ca²⁺ into cells, the activity of the PMCA may be insufficient to remove the excess Ca²⁺.

History

PMCAs were first discovered in the 1960s in the membranes of red blood cells. The presence of an ATPase was discovered in the membranes in 1961, and then in 1966 it was discovered that these ATPases pump Ca²⁺ out of the cytosol.

External links

• Plasma+Membrane+Calcium-Transporting+ATPases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)