Extracellular calcium-dependent regulation of transmembrane calcium fluxes in murine keratinocytes

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Abstract
Because the level of extracellular Ca2+ is an important stimulus for differentiation of epidermal cells in vitro, we characterized the extracellular Ca2+ ‐dependent transmembrane Ca2+ fluxes in BALB/MK mouse keratinocytes. Increasing levels of extracellular Ca2+ ranging from 0.07 to 1.87 mM, stimulated the rate of 45Ca2+ uptake into these cells 10‐ to 70‐fold and doubled the rate of 45Ca2+ efflux. The divalent cations, Ni2+ and Co2+, were able to block the influx of Ca2+, but dihydropyridines and verapamil were not. Furthermore, 10 to 100 μM of the trivalent cation La3+ induced a dose‐dependent 2‐ to 100‐fold increase of Ca2+ uptake, independently of the level of extracellular Ca2+. These observations suggest that keratinocytes possess a cell‐surface “Ca2+ ‐receptor,” activation of which stimulates the influx of 45Ca2+ through a type of voltage‐independent, receptor‐operated Ca2+ channels. Epidermal growth factor induced an accumulation of 45Ca2+ of a much smaller magnitude than elevations of the level of extracellular Ca2+, without a detectable increase of Ca2+ efflux. Thus, the divergent cellular responses of keratinocytes to EGF and extracellular Ca2+ may be due, in part, to the distinct changes in transmembrane Ca2+ fluxes that these two stimuli generate. Treatment of cells with type β transforming growth factor led to a gradual 6‐fold increase of the Ca2+ ‐activated rate of Ca2+ uptake over a period of 4 hours, but reduced the Ca2+ efflux by approximately 50% within 10 minutes. Thus, type β transforming growth factor apparently stimulates Ca2+ influx indirectly, but may control the differentiation of keratinocytes by direct inhibition of Ca2+ efflux pumps.