Cell Calcium 35 (2004) 257–264 Calcium-sensing receptor in the brain Shozo Yano ∗ , Edward M. Brown, Naibedya Chattopadhyay Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA Received 20 October 2003; accepted 27 October 2003 Abstract Following its cloning through an homology-based method from a rat striatal library, the calcium-sensing receptor (CaR) has been localized in the brains of adult and developing rats by immunocytochemistry and in situ hybridization with CaR-specific antibodies and cDNA probes, respectively. The receptor resides in numerous regions of the brain at widely varying levels. The highest levels are present within the subfornical organ (SFO) and the olfactory bulbs. Substantial levels of expression are also evident within the hippocampus, striatum, cingulate cortex, cerebellum, ependymal zones of the cerebral ventricles, and perivascular nerves around cerebral arteries. There are abundant levels of CaR expression within the SFO, an important hypothalamic thirst center, suggesting that it participates in the central control of systemic fluid and electrolyte balance. Therefore, while mineral ion homeostasis is not often considered to have central regulatory elements (i.e. in the brain), there are perhaps more complex relationships than recognized previously among the system governing mineral ion homeostasis and other homeostatic systems known to exhibit prominent neuroendocrine elements (i.e. water homeostasis). Furthermore, the expression of the CaR in all three types of glial cells indicates potential roles in the maintenance of local ionic homeostasis as well as in disease processes such as glioma. © 2003 Elsevier Ltd. All rights reserved. Keywords: Subfornical organ; Ca 2+ -activated K + channel; Nonselective cation channel; Oligodendrocyte; Glioma; Microglia 1. Introduction Calcium acts as an extra- and intracellular messenger molecule mediating adaptive changes in neuroarchitecture in response to signals such as neurotransmitters and neu- rotrophic factors. In the brain, calcium is also involved in long-term adaptive processes, such as memory. Such adap- tive changes require an optimal range of intracellular Ca 2+ (Ca 2+ i ) and play major roles during development and in the plasticity of the adult nervous system [1,2]. However, Ca 2+ i levels that are too high for too long can cause maladaptive degradation of cellular components by mechanisms not yet fully understood. The source of the messenger calcium is either the normally abundant extracellular Ca 2+ (Ca 2+ ), or intracellular pools, such as the endoplasmic reticulum (ER), mitochondria and the so-called calciosomes (the site for calcium-triggered calcium release) [2]. Thus, calcium home- ostasis in the CNS is maintained by Ca 2+ entry into neural cells via voltage-sensitive or ligand-gated calcium channels and by Ca 2+ release from the ER and mitochondria. ∗ Corresponding author. E-mail address: syano@rics.bwh.harvard.edu (S. Yano). The mechanisms regulating cellular Ca 2+ homeosta- sis that have been most widely studied include various aspects of the control of Ca 2+ i by Ca 2+ influx (e.g. by receptor-mediated or voltage-dependent mechanisms) and by Ca 2+ release from intracellular stores, as well as cy- tosolic Ca 2+ buffering and downstream events involving Ca 2+ i -activated signaling proteins. A more recent addi- tion to this complex scheme is the possible participation of the calcium-sensing receptor (CaR) in regulating var- ious aspects of cellular function within the CNS [3–5]. The CaR, a member of family C G-protein-coupled, seven transmembrane receptors, is predominantly expressed on the cell membrane [4,5]. This receptor does not have an EF hand, which is characteristic in intracellular neuronal calcium sensor proteins. The CaR binds extracellular Ca 2+ with relatively low affinity and also binds a variety of other ligands. Nevertheless, the receptor has important bi- ological roles in regulating the metabolism of Ca 2+ and perhaps other ions as well as in water balance in the body [5,6]. Recent evidence suggests that the brain has an in- tegrating function in mineral homeostasis by virtue of the CaR’s monitoring of circulating levels of Ca 2+ and other cations. 0143-4160/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.ceca.2003.10.008