Distinct phenotypes among plasma membrane Ca2+-ATPase knockout mice.

Ca2+ gradients across the plasma membrane, required for Ca2+ homeostasis and signaling, are maintained in part by plasma membrane Ca2+-ATPase (PMCA) isoforms 1-4. Gene targeting has been used to analyze the functions of PMCA1, PMCA2, and PMCA4 in mice. PMCA1 null mutant embryos die during the preimplantation stage, and loss of a single copy of the PMCA1 gene contributes to apoptosis in vascular smooth muscle. PMCA2 deficiency in sensory hair cells of the inner ear causes deafness and balance defects, most likely by affecting both intracellular Ca2+ and extracellular Ca2+ in the endolymph. PMCA2 is required for viability of certain neurons, consistent with a major role in maintenance of intracellular Ca2+. Surprisingly, loss of PMCA2 in lactating mammary glands causes a sharp reduction in milk Ca2+, consistent with a macrocalcium secretory function. Although PMCA4 is widely expressed and is the most abundant isoform in some tissues, null mutants appear healthy. However, male PMCA4 null mutants are infertile due to a failure of hyperactivated sperm motility resulting from the absence of PMCA4 in the sperm tail, and Ca2+ signaling in B lymphocytes, involving interactions between PMCA4, CD22, and the tyrosine phosphatase SHP-1, is defective. Studies of bladder smooth muscle from PMCA4 null mutants and PMCA1 heterozygous mice suggest that PMCA1 and PMCA4 play different roles in smooth muscle contractility, with PMCA1 contributing to overall Ca2+ clearance and PMCA4 being required for carbachol-stimulated contraction. These phenotypes indicate that PMCA1 serves essential housekeeping functions, whereas PMCA4 and particularly PMCA2 serve more specialized physiological functions.