Dd. Bikle et al., CHANGES IN CALCIUM RESPONSIVENESS AND HANDLING DURING KERATINOCYTE DIFFERENTIATION - POTENTIAL ROLE OF THE CALCIUM RECEPTOR, The Journal of clinical investigation, 97(4), 1996, pp. 1085-1093
Extracellular calcium concentrations (Cao) > 0.1 mM are required for t
he differentiation of normal human keratinocytes in culture. Increment
s in Cao result in acute and sustained increases in the intracellular
calcium level (Cai), postulated to involve both a release of calcium f
rom intracellular stores and a subsequent increase in calcium influx t
hrough nonspecific cation channels. The sustained rise in Cai appears
to be necessary for keratinocyte differentiation. To understand the me
chanism by which keratinocytes respond to Cao, we measured the acute e
ffects of Cao on Cai and calcium influx in keratinocytes at various st
ages of differentiation. We then demonstrated the existence of the cal
cium receptor (CaR) in keratinocytes and determined the effect of calc
ium-induced differentiation on its mRNA levels. Finally, we examined t
he role of Cai in regulating both the initial rise in Cai after the sw
itch to higher Cao and the activity of the nonspecific cation channel
through which calcium influx occurs. Our data indicate that the acute
Cai response to Cao is lost as the cells differentiate and increase th
eir basal Cai. These data correlated with the decrease in CaR mRNA lev
els in cells grown in low calcium. However, calcium influx as measured
by Ca-45 uptake increased with differentiation in 1.2 mM calcium, con
sistent with the increase in CaR mRNA in these cells as well as the ca
lcium-induced opening of the nonspecific cation channels. We conclude
that the keratinocyte contains a CaR that regulates both the initial r
elease of Cai from intracellular stores and the subsequent increase in
calcium flux through nonspecific calcium channels. A rising level of
Cai may turn off the release of calcium from intracellular stores whil
e potentiating the influx through the nonspecific cation channels. Dif
ferentiation of keratinocytes appears to increase the CaR, which may f
acilitate the maintenance of the high Cai required for differentiation
.