The extracellular calcium concentration determines the rate and extent of keratinocyte differentiation. To determine the mechanism by which keratinocytes sense the extracellular calcium concentration we evaluated the possibility that these cells contained a calcium receptor (CaR) similar or identical to that recently found in the parathyroid gland. Using primers based on the a partial sequence of the human CaR gene we obtained a fragment from human keratinocyte RNA of the expected length (870 bp) which was 95% homologous to the same region of the bovine CaR (the human sequence has not yet been published in full). We then determined the influence of differentiation on the levels of the mRNA for CaR by evaluating these levels at different times of growth (up to three weeks) in medium containing 0.03, 0.1, and 1.2mM calcium, comparing normal human keratinocytes (NHK) to the transformed cell line SCC 4 which does not differentiate in response to calcium. In NHK grown in 0.03mM calcium, the CaR mRNA levels decreased with time in culture corresponding to the loss of calcium induced changes in intracellular free calcium (Cai). In contrast in NHK grown in 1.2mM calcium, CaR mRNA levels increased corresponding to the rise in Cai and calcium induced calcium influx observed with differentiation. At 0.1mM calcium, the CaR mRNA levels remained constant during the three week period. In SCC 4 cells, CaR mRNA levels did not vary with time or calcium concentration. Our data demonstrate the presence of the CaR mRNA in keratinocytes, and document its regulation by calcium during differentiation. The precise role of the CaR in regulating the cellular response to calcium is under active investigation.