• embryonic stem cells;
  • gene targeting;
  • ATP2A1;
  • ATP2A2;
  • ATP2A3;
  • ATP2B1;
  • ATP2B2;
  • ATP2B3;
  • ATP2B4;
  • ATP2C1

Abstract: It is known that plasma membrane Ca2+-transporting ATPases (PMCAs) extrude Ca2+ from the cell and that sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs) and secretory pathway Ca2+-ATPases (SPCAs) sequester Ca2+ in intracellular organelles; however, the specific physiological functions of individual isoforms are less well understood. This information is beginning to emerge from studies of mice and humans carrying null mutations in the corresponding genes. Mice with targeted or spontaneous mutations in plasma membrane Ca2+-ATPase isoform 2 (PMCA2) are profoundly deaf and have a balance defect due to the loss of PMCA2 in sensory hair cells of the inner ear. In humans, mutations in SERCA1 (ATP2A1) cause Brody disease, an impairment of skeletal muscle relaxation; loss of one copy of the SERCA2 (ATP2A2) gene causes Darier disease, a skin disorder; and loss of one copy of the SPCA1 (ATP2C1) gene causes Hailey-Hailey disease, another skin disorder. In the mouse, SERCA2 null mutants do not survive to birth, and heterozygous SERCA2 mutants have impaired cardiac performance and a high incidence of squamous cell cancers. SERCA3 null mutants survive and appear healthy, but endothelium-dependent relaxation of vascular smooth muscle is impaired and Ca2+ signaling is altered in pancreatic β cells. The diversity of phenotypes indicates that the various Ca2+-transporting ATPase isoforms serve very different physiological functions.