Plasma membrane Ca2+ ATPase

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File:Calcium atpase.png
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.[1] In fact, the PMCA is involved in removing Ca2+ from all eukaryotic cells.[2] 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+.[3] The PMCA and the sodium calcium exchanger (NCX) are together the main regulators of intracellular Ca2+ concentrations.[2] Since it transports Ca2+ into the extracellular space, the PMCA is also an important regulator of the calcium concentration in the extracellular space.[4]

The PMCA belongs to a family of P-type primary ion transport ATPases that form an aspartyl phosphate intermediate.[2]

The PMCA is expressed in a variety of tissues, including the brain.[5]

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 Km of 100 to 200 nM) but does not remove Ca2+ at a very fast rate.[6] 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.[3] Calcium is an important second messenger, so its levels must be kept low in cells to prevent noise and keep signalling accurate.[7] 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.[3] ATP transfers a phosphate to the PMCA, which forms a phosphorylated intermediate.[3]

Ca2+/calmodulin binds and further activates the PMCA, increasing the affinity of the protein's Ca2+ binding site 20 to 30 times.[6] Calmodulin also increases the rate at which the pump extrudes Ca2+ from the cell, possibly up to ten fold.[3]

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,[5] 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.[2] 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.[2] At the C terminus, there is a long "tail" of between 70 and 200 amino acids in length.[2] This tail is thought to be responsible for regulation of the pump.[2]

Isoforms

There are four isoforms of PMCA, called PMCA 1 through 4.[5]

Each isoform is coded by a different gene and is expressed in different areas of the body.[5] Alternate splicing of the mRNA transcripts of these genes results in different subtypes of these isoforms.[2] Over 20 splice variants have been identified so far.[2]

Three PMCA isoforms, PMCA1, PMCA2, and PMCA3, occur in the brain in varying distributions.[6] PMCA1 is ubiquitous throughout all tissues in humans, and without it embryos do not survive.[4] Lack of PMCA4, which is also very common in many tissues, is survivable, but leads to infertility in males.[4] 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.[5] 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. [8] 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.[9]

PMCA4 exists in caveolae.[9] Isoform PMCA4b interacts with nitric oxide synthase and reduces synthesis of nitric oxide by that enzyme.[9]

PMCA isoforms 1, 2 and 4 probably weigh about 153 kDa each.[10]

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.[4]

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.[2] 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.[3]

References

  1. Jensen, TP (2004). "Expression of plasma membrane Ca2+ ATPase family members and associated synaptic proteins in acute and cultured organotypic hippocampal slices from rat". Brain Research. Developmental Brain Research. 152 (2): 129–136. PMID 15351500. Unknown parameter |coauthors= ignored (help); |access-date= requires |url= (help)
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 Strehler, EE (2001). "Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps". Physiological Reviews. American Physiological Society. 81 (1): 21–50. PMID 11152753. Retrieved 2007-01-30. Unknown parameter |coauthors= ignored (help)
  3. 3.0 3.1 3.2 3.3 3.4 3.5 Carafoli, E (1991). "Calcium pump of the plasma membrane". Physiological Reviews. 71 (1): 129–153. PMID 1986387. Retrieved 2007-01-30.
  4. 4.0 4.1 4.2 4.3 Talarico Jr, EF (2005). "Expression and immunolocalization of plasma membrane calcium ATPase isoforms in human corneal epithelium". Molecular Vision. 11: 169–178. Unknown parameter |coauthors= ignored (help)
  5. 5.0 5.1 5.2 5.3 5.4 Jensen, TP (2006). "Pre-synaptic plasma membrane Ca2+ ATPase isoform 2a regulates excitatory synaptic transmission in rat hippocampal CA3". Journal of Physiology: Published online ahead of print. 17170045. Retrieved 2007-01-13. Unknown parameter |coauthors= ignored (help)
  6. 6.0 6.1 6.2 Siegel, GJ (1999). Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. 6th ed. Philadelphia: Lippincott,Williams & Wilkins. Unknown parameter |coauthors= ignored (help) Retrieved on January 13, 2007.
  7. Burette, A (2007). "Perisynaptic organization of plasma membrane calcium pumps in cerebellar cortex". Journal of Comparative Neurology. 500 (6): 1127–1135. PMID 17183553. Unknown parameter |coauthors= ignored (help); |access-date= requires |url= (help)
  8. Fresu, L (1999). "Plasma membrane calcium ATPase isoforms in astrocytes". Glia. 28 (2): 150–155. PMID 10533058. Unknown parameter |coauthors= ignored (help); |access-date= requires |url= (help)
  9. 9.0 9.1 9.2 Schuh, K (2001). "The plasmamembrane calmodulin–dependent calcium pump : a major regulator of nitric oxide synthase I". Journal of Cell Biology. The Rockefeller University Press. 155 (2): 201–205. doi:doi 10.1083 Check |doi= value (help). PMID 11591728. Retrieved 2007-01-30. Unknown parameter |coauthors= ignored (help)
  10. Yang, H (2005). "Detection of molecular weight of PMCA isoform with 20 cm SDS PAGE electrophoresis: compared with 8 cm SDS PAGE". Yan Ke Xue Bao (Eye Science). 21 (3): 179–184. PMID 17162858. Unknown parameter |coauthors= ignored (help); |access-date= requires |url= (help)

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