Voltage-gated Ca1 and Ca2 Ca channels are comprised of a pore-forming a1 subunit (Ca1.1-1.4, Ca2.1-2.3) and auxiliary β (β) and αδ (αδ-1-4) subunits. The properties of these channels vary with distinct combinations of Casubunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Ca subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type 2 (CSNB2)-causing mutation, I745T (IT), in Ca1.4 channels typical of those in human retina: Ca1.4 splice variants with or without exon 47 (Ca1.4+ex47, Ca1.4Δex47, respectively), and the auxiliary subunits, β and α2δ-4. We find that IT caused both Ca1.4 splice variants to activate at significantly more negative voltages and with slower deactivation kinetics than the corresponding WT channels. These effects of the IT mutation, along with unexpected alterations in ion selectivity, were generally larger in channels lacking exon 47. The weaker ion selectivity caused by IT led to hyperpolarizing shifts in the reversal potential and large outward currents that were evident in channels containing the auxiliary subunits β and αδ-4 but not in those with β and αδ-1. We conclude that the IT mutation stabilizes channel opening and alters ion selectivity of Ca1.4 in a manner that is strengthened by exclusion of exon 47 and inclusion of β and αδ-4. Our results reveal complex actions of IT in modifying the properties of Ca1.4 channels, which may influence the pathological consequences of this mutation in retinal photoreceptors.
Published under license by The American Society for Biochemistry and Molecular Biology, Inc.