Channel to the Nucleus?

Science's STKE  07 Nov 2006:
Vol. 2006, Issue 360, pp. tw376
DOI: 10.1126/stke.3602006tw376

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 Cav1.2 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 Cav1.2 C terminus was fluorescently labeled. Treatments aimed at lowering cytoplasmic calcium increased nuclear abundance of the Cav1.2 fragment, whereas treatments that increase intracellular calcium decreased it. The Cav1.2 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 Cav1.2 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 CaV1.2 encodes a transcription factor. Cell 127, 591-606 (2006). [PubMed]