Regulation of intracellular calcium is crucial both for proper neuronal function and survival. By coupling ATP hydrolysis with Ca 2+ extrusion from the cell, the plasma membrane calciumdependent ATPases (PMCAs) play an essential role in controlling intracellular calcium levels in neurons. In contrast to PMCA2 and PMCA3, which are expressed in significant levels only in the brain and a few other tissues, PMCA1 is ubiquitously distributed, and is thus widely believed to play a "housekeeping" function in mammalian cells. Whereas the PMCA1b splice variant is predominant in most tissues, an alternative variant, PMCA1a, is the major form of PMCA1 in the adult brain. Here, we use immunohistochemistry to analyze the cellular and subcellular distribution of PMCA1a in the brain. We show that PMCA1a is not ubiquitously expressed, but rather is confined to neurons, where it concentrates in the plasma membrane of somata, dendrites and spines. Thus, rather than serving a general "housekeeping" function, our data suggest that PMCA1a is a calcium pump specialized for neurons, where it may contribute to the modulation of somatic and dendritic Ca 2+ transients.Keywords calcium extrusion; calcium pump; immunohistochemistry; Cell Centered Database Transient changes in the intracellular concentration of free calcium ([Ca 2+ ] i ) act to regulate or control numerous neuronal processes ranging from electrical excitability and neurotransmitter release (Neher and Sakaba, 2008, Spitzer et al., 2002), to dendritic integration and gene expression (Cohen and Greenberg, 2008, Larkum andNevian, 2008). This versatility requires an elaborate "toolkit" of proteins to control the influx, efflux, and buffering of Ca 2+ within and between cellular compartments, creating signals with widely different spatial and temporal profiles (Berridge et al., 2000;Friel and Chiel, 2008 (Berliocchi et al., 2005). Perturbation of Ca 2+ homeostasis is implicated in a variety of neuropathologies including stroke and Alzheimer's disease (Bezprozvanny and Mattson, 2008;Mattson, 2007). Not surprisingly, neurons use multiple strategies to deal with Ca 2+ loads, including buffers (Schwaller et al., 2002), intracellular sinks (Verkhratsky, 2002), and membrane extrusion systems (Lytton, 2007;Strehler, 1990). As the sole high-affinity Ca 2+ extrusion mechanism in the plasma membrane, the plasma membrane Ca 2+ ATPases (PMCAs) play a key role in regulating [Ca 2+ ] i (Di Leva et al., 2008).Mammals express four isoforms of PMCA, encoded by four different genes (ATP2B1-4 in humans). The transcripts of these genes are subject to developmental and tissue-specific alternative splicing, resulting altogether in over 20 PMCA variants (Strehler and Zacharias, 2001). In vitro studies show that each isoform differs in its kinetics and affinity for Ca 2+ and calmodulin. However, availability of calmodulin is but one of the factors that regulate PMCA activity in vivo. The isoforms also are differentially regulated by phosphorylation (e.g., via protein kinases A and C), by prote...