The Plasma Membrane Calcium ATPases in Calcium Signaling Network

The plasma membrane Ca2+ ATPases (PMCAs) are responsible for the clearance of Ca2+ out of cells after intracellular Ca2+ transients. Cooperating with Na+/Ca2+ exchangers (NCXs) and Ca2+ buffering proteins, PMCAs play an essential role in maintaining the long-term cellular Ca2+ homeostasis. The plasma membrane Ca2+ ATPase was first discovered in red blood cell membrane about 50 years ago, and then other PMCA isoforms and alternatively spliced variants had been identified from different tissues and different developmental stages, revealing a surprising complexity of the PMCA family. In mammals, there are four PMCA isoforms encoded by four distinct genes. Isoform 1 and 4 are found in virtually all tissues, whereas isoform 2 and 3 are primarily expressed in excitable cells such as neurons and myocytes. Perturbation of PMCAs function has been implicated in a variety of diseases and disorders, including hearing loss, ataxia, paraplegia, and infertility. Here, we would like to review the recent progresses in the study of the PMCAs and related disorders, in particular how these pathological conditions help us to gain an in-depth insight into the function of PMCAs and their contribution in the regulation of Ca2+ signaling network.