The calcium-sensing receptor (CaSR) is a member of a growing family of heptahelical receptors with an unusually large extracellular domain. To further delineate its functions in neurons and glia, we have investigated the expression pattern of CaSR transcripts in the postnatal and adult rat brain, spinal cord and dorsal root ganglia by in situ hybridization. CaSR-expressing cells were spatially and temporally regulated in myelinated structures with a caudo-rostral pattern that paralleled that of myelin basic protein, a marker of myelination, with a downregulation observed in the adult. Double-labelling studies demonstrated that CaSR mRNA colocalizes with myelin basic protein-expressing cells within fibre tracts, suggesting that CaSR is expressed by mature oligodendrocytes. In cultured rat oligodendrocytes, Ca2+ induced stimulation of phosphatidylinositol hydrolysis with an EC50 of 1.4 mM and increased intracellular calcium. NPS R-568 (1 microM), a calcimimetic, significantly stimulates the inositol phosphate response, whereas a less potent stereoisomer, NPS S-568 (1 microM), was without effect. These data suggest that a functional CaSR is expressed in mature oligodendrocytes with a potential role in myelination. CaSR expression was also developmentally regulated in neurons of the orbital cortex and in the CA2 region of the hippocampus, and present in olfactory nuclei, hypothalamic areas and in the area postrema through postnatal days to adulthood. This expression is consistent with a role of CaSR in olfactory or gustatory signal integration, and with the regulation of fluid and mineral homeostasis. CaSR expression in a subpopulation of small cells in dorsal root ganglia suggests additional roles for extracellular Ca2+ in sensory nerves.