title: Physiological functions of plasma membrane and intracellular Ca2+ pumps revealed by analysis of null mutants.
abstract: It is known that plasma membrane Ca(2+)-transporting ATPases (PMCAs) extrude Ca(2+) from the cell and that sarco(endo)plasmic reticulum Ca(2+)-ATPases (SERCAs) and secretory pathway Ca(2+)-ATPases (SPCAs) sequester Ca(2+) 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 Ca(2+)-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 Ca(2+) signaling is altered in pancreatic beta cells. The diversity of phenotypes indicates that the various Ca(2+)-transporting ATPase isoforms serve very different physiological functions.
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Ohio 45267, USA. shullge@ucmail.uc.edu
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.forename: Gbolahan
authors.initials: G
authors.lastname: Okunade
authors.forename: Lynne H
authors.initials: LH
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: Kozel
authors.forename: Muthu
authors.initials: M
authors.lastname: Periasamy
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
authors.forename: Vikram
authors.initials: V
authors.lastname: Prasad
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000252:Calcium-Transporting ATPases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D027682:Cation Transport Proteins; D002462:Cell Membrane / Q000201:enzymology; D003638:Deafness / Q000201:enzymology / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053499:Plasma Membrane Calcium-Transporting ATPases; D016415:Sequence Alignment; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
chemical_list: D027682:Cation Transport Proteins; D053499:Plasma Membrane Calcium-Transporting ATPases; C506958:ATP2B2 protein, human; C506959:Atp2b2 protein, mouse; D000252:Calcium-Transporting ATPases