Plasma membrane Ca2+ ATPase

The plasma membrane Ca²⁺ ATAase (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. Since it transports Ca²⁺ into the extracellular space, the pump is also an important regulator of extracellular calcium concentration. The PMCA is expressed in a variety of cell types, including brain.

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The pump is powered by the hydrolysis of adenosine triphosphate (ATP), with a stoichiometry of one Ca²⁺ ion 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 sodium calcium exchanger (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.

Ca²⁺/calmodulin binds and further activates the PMCA, increasing the affinity of the protein's Ca²⁺ binding site 20 to 30 times.

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.

Isoforms

There are four isoforms of PMCA, called PMCA 1 through 4. Each isoform is coded by a different gene and is expressed in different areas of the body. Three types, 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 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⁺.