Neuronal calcium-binding proteins (CaBP1-8) belong to a subclass of the calmodulin (CaM) superfamily and regulate in particular Ca²⁺ channel targets in the brain and retina¹.

CaBP4 contains two globular domains (N- and C-lobe) that each contains a pair of EF- hand motifs connected by a central linker. The second EF-hand in CaBP4 lacks conserved residues in the binding loop and is predicted to not bind Ca²⁺. CaBP4 interacts structurally with the C-terminal region of Ca_V1.4 and this Ca²⁺-dependent interaction has been implicated in the modulation of voltage-dependent Ca_V1.4 activation².

Multiple isoforms of CaBPs are localized in different neuronal cell types and perform specialized roles in signal transduction. The CaBP4 isoform regulates voltage-gated Ca²⁺ channels in retinal photoreceptor cells. In the eye, CaBP4 is localized at the photoreceptor synaptic terminals in rods and cones³. CaBP4 is essential for the development and maintenance of the photoreceptor synapse, likely through functional modulation of the photoreceptor Ca²⁺ channels, α1F L-type voltage- dependent calcium channels (Ca_V1.4), and neurotransmitter release⁴.

Mutations in both Ca_V1.4 and CaBP4 have been identified in patients suffering from congenital stationary night blindness type 2 (CSNB2), indicating that defects in Ca²⁺-dependent regulation of Ca_V1.4 by CaBP4 are closely associated with CSNB2. Indeed, deletion of CaBP4 in the mouse leads to a CSNB2-like phenotype⁵.