Channels Channel to the Nucleus?

Elizabeth M. Adler

Science's STKE, AAAS, Washington, DC 20005, USA

Gomez-Ospina et al. provide evidence for an intriguing mechanism whereby voltage-dependent calcium channels modulate gene transcription. Calcium entry through voltage-gated channels in the plasma membrane provides a link between electrical activity and changes in gene expression. Gomez-Ospina et al. found that, whereas an antibody that recognized the full-length Ca_v1.2 calcium channel localized to membrane and cytosolic fractions of rat brain cortex, an antibody that recognized the C-terminal fragment, which is proteolytically cleaved, appeared in the nucleus. The C-terminal fragment was abundant in nuclei of GABAergic neurons; moreover, nuclear fluorescence was apparent in neurons or glioblastoma cells expressing a construct in which the Ca_v1.2 C terminus was fluorescently labeled. Treatments aimed at lowering cytoplasmic calcium increased nuclear abundance of the Ca_v1.2 fragment, whereas treatments that increase intracellular calcium decreased it. The Ca_v1.2 fragment immunoprecipitated with p54(nrb)/NonO, a nuclear protein, and, when recruited to the promoter with a heterologous DNA binding domain, transcriptionally activated a gene reporter. Overexpression of the fragment, which the authors called calcium channel associated transcription regulator (CCAT), led to an increase in the expression of some endogenous genes and a decrease in the expression of others. CCAT overexpression increased the abundance of mRNA encoding the gap junction protein Cx31.1 and transcriptionally activated a reporter containing the Cx31.1 promoter; chromatin immunoprecipitation analysis indicated that it associated with the Cx31.1 promoter. Furthermore, decreasing the abundance of endogenous nuclear CCAT either by depolarization or with short hairpin RNA led to a decrease in transcription of the Cx31.1 reporter. Thus, the authors conclude that the proteolytically cleaved C terminus of Ca_v1.2 translocates to the nucleus to act as a transcription factor.

N. Gomez-Ospina, F. Tsuruta, O. Barreto-Chang, L. Hu, R. Dolmetsch, The C terminus of the L-type voltage-gated calcium channel Ca_V1.2 encodes a transcription factor. Cell 127, 591-606 (2006). [PubMed]