The β Subunit of Voltage-Gated Ca2+ Channels Acts as a Transcriptional Regulator

Ca2+ channel β subunits (Cavβs) are essential for the surface expression and proper gating of high-voltage activated (HVA) Ca2+ channels. In yeast two-hybrid screens aimed at discovering novel Cavβ-interacting proteins, we identified a new splicing isoform of Pax6, a transcription factor crucial for the development of a variety of organs and tissues, especially the eye. Pax6 contains two DNA-binding domains (paired domain and homeodomain), a glycine-rich linker connecting these two domains, and a carboxyl (C)-terminal proline, serine and threonine (PST)-rich transactivation domain. The newly isolated isoforms, named Pax6(S), retains the paired domain, linker and homeodomain of Pax6, but its C-terminus is composed of a truncated classic PST domain and a unique S tail. In contrast to Pax6, which is 100% conserved from rodent to human and is expressed in both embryo and adult, Pax6(S) is completely conserved only in human and chimpanzee, and it is expressed only at early stages of development, suggesting that Pax6(S) has a noncanonical function. Pax6(S) retained strong transcriptional activity, although its C-terminus showed less transactivity compared with the canonical PST domain. The interaction between Pax6(S) and Cavβ was mainly endowed by the S tail of Pax6(S). Co-expression of Pax6(S) with a HVA Ca2+ channel complex containing the β3 subunit in Xenopus oocytes did not affect channel properties. However, the transcriptional activity of Pax6(S) was markedly suppressed by β3. Furthermore, in the presence of Pax6(S), β3 was translocated from the cytoplasm to the nucleus. These results suggest that full length Cavβs may function as transcription regulators, independent of their role in regulating Ca2+ channel activity.