A novel calcium channel Cav2 splice variant with unique properties predominates in the retina

Cav[1 subunits are essential for surface expression of voltage-gated calcium channel complexes and crucially modulate biophysical properties like voltage-dependent inactivation. Here, we describe the discovery and characterization of a novel Cav[12 variant with distinct features that predominates in the retina. We determined spliced exons in retinal transcripts of the Cacnb2 gene, coding for Cav[12, by RNA-Seq data analysis and quantitative PCR. We cloned a novel Cav[12 splice variant from mouse retina, which we are calling [12i, and investigated biophysical properties of calcium currents with this variant in a heterologous expression system as well as its intrinsic mem-brane interaction when expressed alone. Our data showed that [12i predominated in the retina with expression in photore-ceptors and bipolar cells. Furthermore, we observed that the [12i N-terminus exhibited an extraordinary concentration of hydrophobic residues, a distinct feature not seen in canonical variants. The biophysical properties resembled known membrane-associated variants, and [12i exhibited both a strong membrane association and a propensity for clustering, which depended on hydrophobic residues in its N-terminus. We considered available Cav[1 structure data to elucidate potential mechanisms underlying the observed characteristics but resolved N-terminus structures were lacking and thus, pre-cluded clear conclusions. With this description of a novel N-terminus variant of Cav[12, we expand the scope of functional variation through N-terminal splicing with a distinct form of membrane attachment. Further investigation of the molecular mechanisms underlying the features of [12i could provide new angles on the way Cav[1 subunits modulate Ca2+ channels at the plasma membrane.