Differential regulation of mitogen-activated protein kinase-responsive genes by the duration of a calcium signal

We have investigated the cellular mechanisms by which changes in intracellu lar calcium (Ca2+) can differentially regulate gene expression. Two Ca2+ pa radigms, involving prolonged and transient Ca2+ increases, were used. As a starting point, we studied the slow, prolonged elevation of Ca2+ caused by activation of 5-HT1 receptors, We had previously shown that 5-HT1 agonists inhibit calcitonin gene-related peptide (CGRP) transcription and secretion. The Ca2+ ionophore, ionomycin, was used to produce a prolonged elevation o f the Ca2+ signal similar to that generated by 5-HT1 receptor agonists. Ion omycin treatment of the neuronal-like CA77 cell line specifically inhibited mitogen-activated protein (MAP) kinase stimulation of the CORP enhancer an d two synthetic MAP kinase-responsive reporter genes (4- to 10-fold). We th en showed that ionomycin repression of promoter activity involved selective induction of MAP kinase phosphatase-1 (MKP-1), but not MKP-2, and that ove rexpression of MKP-1 was sufficient to repress CORP enhancer activity. Thes e effects were then compared with a Ca2+ paradigm involving a transient ele vation in Ca2+ as seen after depolarization. At 4 h after the transient inc rease in Ca2+, the CORP enhancer and synthetic MAP kinase-responsive report er genes were stimulated. In contrast, exposure to depolarizing stimuli ove rnight caused only a less than 2-fold inhibition of promoter activity. We p ropose that the duration of the Ca2+ signal can determine the magnitude of a negative feedback loop that leads to differential regulation of MAP kinas e-responsive genes.