Abstract
Although it has been established that an activity-dependent gene transcription is induced by the calcium (Ca(2+)) signals in neurons, it is unclear how the specific mRNA moieties are transiently accumulated in response to synaptic transmission which evokes multiple intracellular signals including Ca(2+) and cAMP ones. The expression of pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide, is controlled by Ca(2+) signals evoked via membrane depolarization in neurons, and, in cultured rat cortical neuronal cells, we found that the Ca(2+) signal-mediated activation of the PACAP gene promoter was critically controlled by a single cAMP-response element (CRE) located at around -200, to which the CRE-binding protein predominantly bound. The Ca(2+) signal-induced expression of PACAP mRNA was enhanced by forskolin, which evokes cAMP signals. In support, the PACAP gene promoter was synergistically enhanced by Ca(2+) and cAMP signals through the CRE, accompanying a prolonged activation of extracellular signal-related protein kinase 1/2 and CRE-binding protein. On the other hand, sole administration of forskolin markedly reduced the cellular content of PACAP mRNA, which was restored by the addition of Ca(2+) signals. We found that the stability of PACAP mRNA was increased in response to Ca(2+) signals but not that of activity-regulated cytoskeleton-associated protein (Arc) mRNA, indicating an activity-dependent stabilization of specific mRNA species in neurons, which can antagonize the regulation mediated by cAMP signals. Thus, the transcriptional activation and mRNA stabilization are coordinately regulated by Ca(2+) and cAMP signals for the cumulative expression of PACAP mRNA in neurons.
Highlights
It has been established that an activity-dependent gene transcription is induced by the calcium (Ca2؉) signals in neurons, it is unclear how the specific mRNA moieties are transiently accumulated in response to synaptic transmission which evokes multiple intracellular signals including Ca2؉ and cAMP ones
The expression of pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide, is controlled by Ca2؉ signals evoked via membrane depolarization in neurons, and, in cultured rat cortical neuronal cells, we found that the Ca2؉ signal-mediated activation of the PACAP gene promoter was critically controlled by a single cAMP-response element (CRE) located at around ؊200, to which the CRE-binding protein predominantly bound
We first assigned the CRE located on the PACAP gene promoter as a Ca2ϩ signal-response element and investigated whether or not synergistic activation could be induced by Ca2ϩ and cAMP signals through the CRE and, whether the stabilization of PACAP mRNA was affected by these signals
Summary
It has been established that an activity-dependent gene transcription is induced by the calcium (Ca2؉) signals in neurons, it is unclear how the specific mRNA moieties are transiently accumulated in response to synaptic transmission which evokes multiple intracellular signals including Ca2؉ and cAMP ones. Changes in Cellular Content of PACAP mRNA Induced by Ca2ϩ and cAMP Signals—Using a quantitative real-time RTPCR, we measured the expression levels of PACAP exon II-V transcripts when the cells were treated with depolarization and/or forskolin for 12 h.
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