Direct interaction with a nuclear protein and regulation of gene silencing by a variant of the Ca(2+)-channel β(4) subunit

The β subunits of voltage-gated Ca(2+) channels are known to be regulators of the channels' gating properties. Here we report a striking additional function of a β subunit. Screening of chicken cochlear and brain cDNA libraries identified β(4c), a short splice variant of the β(4) subunit. Although β(4c) occurs together with the longer isoforms β(4a) or β(4b) in the brain, eye, heart, and lung, the cochlea expresses exclusively β(4c). The association of β(4c) with the Ca(2+)-channel α(1) subunit has slight but significant effects on the kinetics of channel activation and inactivation. Yeast two-hybrid and biochemical assays revealed that β(4c) interacts directly with the chromo shadow domain of chromobox protein 2/heterochromatin protein 1γ (CHCB2/HP1γ), a nuclear protein involved in gene silencing and transcriptional regulation. Coexpression of this protein specifically recruits β(4c) to the nuclei of mammalian cells. Furthermore, β(4c) but not β(4a) dramatically attenuates the gene-silencing activity of chromobox protein 2/heterochromatin protein 1γ. The β(4c) subunit is therefore a multifunctional protein that not only constitutes a portion of the Ca(2+) channel but also regulates gene transcription.