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.

A plant plasma membrane Ca 2+ pump is required for normal pollen tube growth and fertilization

“…As such, aca9͞ACA9 provides a paradigm for exploring the structure and function of all 10 members of this gene family in Arabidopsis, as well as calmodulin-regulated Ca 2ϩ pumps in non-plant systems. For example, a plasma membrane Ca 2ϩ pump has been implicated in the viability of mammalian sperm (7,46), the animal counterpart to the male gametophyte in plants. Thus, our results provide a genetic tool to begin dissecting the role of calmodulin-regulated Ca 2ϩ pumps in plants and animals.…”

“…Both plants and animals use a combination of ion pumps, antiporters, and uniporters to control cytoplasmic Ca 2ϩ dynamics (2,3), including a family of calmodulin-activated Ca 2ϩ -ATPase ion pumps: plasma membrane Ca 2ϩ ATPases (PMCAs) in animals and autoinhibited Ca 2ϩ ATPases (ACAs) in plants (4,5). In mice, phenotypes resulting from knock-out mutants of different PMCAs include hearing and balance defects (for PMCA2), male sterility (for PMCA4), and lethality (for PMCA1) (6,7). A multiplicity of gene-specific phenotypes support the expectation that Ca 2ϩ ATPases have evolved to fulfill multiple cellular functions, some of which are essential for development of multicellular organisms.…”

Haploinsufficiency of Atp2a2, Encoding the Sarco(endo)plasmic Reticulum Ca2+-ATPase Isoform 2 Ca2+ Pump, Predisposes Mice to Squamous Cell Tumors via a Novel Mode of Cancer Susceptibility

“…1, 2). Encoded by the Atp2a2 gene, this pump sequesters Ca 2+ in the ER, and for this reason, its activity is an important regulator of normal Ca 2+ homeostasis and signaling (3). Alterations in Ca 2+ handling are associated with cell proliferation and differentiation (4,5), and perturbations of Ca 2+ homeostasis have been suggested to contribute to the development of cancer (6,7).…”

Mixing model systems: Using zebrafish and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development

“…Animals deficient in PMCA2 show an intact macular epithelium and gelatinous membrane but lack otoconia (Kozel et al, 1998). PMCA2 has been proposed as the primary Ca 2+ pump for maintenance of endolymph Ca 2+ levels, and other Ca 2+ pump mutants have not been shown to affect inner ear development (Shull et al, 2003). It may be that the role of PMCA2 in general maintenance of endolymph Ca 2+ is required for normal otoconial development; alternatively, PMCA2 may have a more direct role in locally increasing Ca 2+ during otoconia formation.…”