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The plasma membrane calcium pump in health and disease

Marisa Brini1, Tito Calì, Denis Ottolini

  • 1Department of Comparative Biomedicine and Food Science, University of Padova, Italy.

The FEBS Journal
|February 19, 2013
PubMed

Insights

Plasma membrane Ca(2+) ATPases (PMCAs) regulate cellular calcium. Genetic defects in PMCAs, particularly PMCA2 and PMCA3, cause human diseases like deafness and ataxia.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Physiology

Background:

  • Plasma membrane Ca(2+) ATPases (PMCAs) are crucial for exporting calcium ions (Ca(2+)) from eukaryotic cells.
  • Mammalian PMCAs are encoded by four genes, with distinct tissue distribution patterns and numerous isoforms generated by alternative splicing.
  • These pumps are classical P-type ATPases, sharing a conserved reaction cycle with other pumps in their family.

Purpose of the Study:

  • To elucidate the structure-function relationships and regulatory mechanisms of PMCAs.
  • To investigate the role of PMCAs in cellular Ca(2+) homeostasis and their involvement in human diseases.
  • To highlight the significance of calmodulin regulation in PMCA activity.

Main Methods:

  • Molecular modeling based on SERCA pump templates to infer PMCA structure.
  • Analysis of calmodulin interaction with PMCA's cytosolic C-terminal tail.
  • Review of genetic studies linking PMCA mutations to specific pathologies.

Main Results:

  • While the 3D structure of PMCAs is not yet solved, molecular modeling suggests conserved structural features with other P-type ATPases.
  • Calmodulin is a key regulator, binding with high affinity to the C-terminal tail, with additional lower-affinity binding sites in some splice variants.
  • Genetic mutations in PMCA genes, especially PMCA2 and PMCA3, are directly linked to human diseases, including deafness and ataxia.

Conclusions:

  • PMCAs are essential for maintaining cellular Ca(2+) balance, and their dysregulation leads to diverse pathologies.
  • PMCA2 mutations are a well-characterized cause of genetic deafness in mice and humans.
  • PMCA3 mutations are implicated in a recently identified cerebellar ataxia, underscoring the critical role of PMCAs in neurological function.
Keywords:
PMCA mutationscerebellar ataxiagenetic deafnessplasma membrane Ca2+ pumpspump isoforms

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