Correlation between Ca(2+) oscillation and cell proliferation via CCK(B)/gastrin receptor.

Gastrin stimulates cell proliferation through the CCK(B) receptor coupled to Gq-protein, whereas the m3 muscarinic receptor, which also couples to Gq, has no trophic effects. In order to elucidate the cause of the difference, we stably transfected CHO cells with human CCK(B) and m3 receptors. Stimulation of the CCK(B), but not the m3 receptor increased cell growth. Activation of MAP kinase via the m3 receptor was to the same extent as that via CCK(B), indicating that there is an initial signaling common to both receptors. Stimulation of either receptor induced a transient increase in [Ca(2+)](i) followed by a sustained plateau phase. After 2 h of stimulation, the [Ca(2+)](i) response to the m3 receptor disappeared, whereas that to the CCK(B) receptor remained as a [Ca(2+)](i) oscillation. Removal of extracellular Ca(2+), which abolished [Ca(2+)](i) oscillation, completely inhibited DNA synthesis via CCK(B). When the C-terminal part of the CCK(B) receptor was truncated, the trophic effect as well as the [Ca(2+)](i) response after 2 h of stimulation disappeared, whereas the chimeric CCK(B) receptor with the C-terminal region of the m3 receptor preserved its ability to elicit both DNA synthesis and [Ca(2+)](i) oscillation. These results suggest that desensitization might be a principal determinant of cell proliferation, and the persistence of the [Ca(2+)](i) response as [Ca(2+)](i) oscillation could be essential for this type of signal transduction.