Neuronal Ca²⁺-binding proteins (CaBP1-5) are a subclass of the calmodulin (CaM) superfamily that regulates specific Ca²⁺ channel targets in the brain and retina. Multiple isoforms of CaBPs are localized in different neuronal cell types and perform specialized roles in sensory transduction and disease processes¹.

CaBP1–5 proteins have four EF hands that form pairs within the N lobe (EF1 and 2) and C lobe (EF3 and 4). The two lobes are structurally independent and connected by a flexible linker. Whereas all four EF hands bind Ca²⁺ in CaM, EF2 in CaBP1 does not bind Ca²⁺, and EF1 has reduced selectivity for Ca²⁺ over Mg²⁺. EF3 and EF4 in the C lobe of CaBP1 exhibit canonical Ca²⁺-induced conformational changes². CaBP-target interactions induce functional changes distinct from those caused by CaM and may diversify neuronal responses to Ca²⁺ signals. CaBPs interact with and reshape the functional properties of certain voltage-gated Ca²⁺ channels (Ca_Vs)³.

CaBP1 is the best characterized family member and has been shown to regulate inositol 1,4,5-triphosphate receptors (IP₃Rs), P/Q-type voltage-gated Ca²⁺ channels, L-type Ca²⁺ channels, and the transient receptor potential channel (TRPC5)⁴. CaBP1 regulates the currents of Ca_V1 and Ca_V2 channels in neurons, photoreceptors, and auditory hair cells. CaBP interactions with Ca_V1 channels may be required for hearing and vision, as mutations that disrupt these interactions cause blindness and deafness⁵.