Abstract
The C-terminus of the voltage-gated calcium channel Cav1.2 encodes a transcription factor, the calcium channel associated transcriptional regulator (CCAT), that regulates neurite extension and inhibits Cav1.2 expression. The mechanisms by which CCAT is generated in neurons and myocytes are poorly understood. Here we show that CCAT is produced by activation of a cryptic promoter in exon 46 of CACNA1C, the gene that encodes CaV1.2. Expression of CCAT is independent of Cav1.2 expression in neuroblastoma cells, in mice, and in human neurons derived from induced pluripotent stem cells (iPSCs), providing strong evidence that CCAT is not generated by cleavage of CaV1.2. Analysis of the transcriptional start sites in CACNA1C and immune-blotting for channel proteins indicate that multiple proteins are generated from the 3′ end of the CACNA1C gene. This study provides new insights into the regulation of CACNA1C, and provides an example of how exonic promoters contribute to the complexity of mammalian genomes.
Highlights
Voltage-gated calcium channels are central regulators of signaling and gene expression in the nervous system
This transcriptional regulation can be mediated by influencing the function of transcription factors like CREB, NFAT, and MEF2 [3,4,5,6,7], or by the activity of channel associated transcriptional regulator (CCAT), a transcription factor encoded within its C-terminal domain
We provide evidence supporting that CCAT is produced not by cleavage of the Cav1.2 channel protein but by an internal promoter in the CACNA1C gene that drives expression of exons 46 and 47 independently
Summary
Voltage-gated calcium channels are central regulators of signaling and gene expression in the nervous system. The Ltype calcium channel Cav1.2 is effective at regulating gene expression in response to depolarization [1,2] This transcriptional regulation can be mediated by influencing the function of transcription factors like CREB, NFAT, and MEF2 [3,4,5,6,7], or by the activity of CCAT, a transcription factor encoded within its C-terminal domain. A putative cleavage site on the C-terminus of Cav1.1, the L-type channel in skeletal muscle, has been identified using mass spectrometry [10]. It is not clear, if a similar mechanism is responsible for generating CCAT in neurons
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
