CABP2

CABP2 encodes a calmodulin-related Ca2+-binding protein that serves as a presynaptic modulator of CaV1.3 voltage-gated calcium channels required for synaptic signal encoding in cochlear inner hair cells and retinal neurons (PMID:22981119, PMID:34489639). CaBP2 directly binds Ca2+ and, through this Ca2+ sensing, suppresses steady-state inactivation of CaV1.3 channels, thereby sustaining calcium channel availability for indefatigable synaptic transmission (PMID:22981119, PMID:34489639). A truncating splice-site mutation that disrupts Ca2+ binding weakens CaV1.3 regulation, linking CaBP2 loss of function to autosomal-recessive deafness (DFNB93) (PMID:22981119). In Cabp2 knockout mice, loss of CaBP2 produces enhanced CaV1.3 inactivation, elevated auditory brainstem response thresholds, and reduced otoacoustic emissions, while AAV-mediated re-expression of Cabp2 in inner hair cells reverses the enhanced channel inactivation and restores hearing (PMID:34489639, PMID:29661613). CaBP2 additionally shapes retinal ganglion cell light-response amplitude and kinetics through presynaptic Ca2+-dependent signaling without being required for ribbon synapse structural integrity (PMID:27822497).

1. 2012 High

   Established that CaBP2 regulates CaV1.3 channels through its Ca2+-binding capacity by showing a disease-associated truncation impairs both Ca2+ binding and channel modulation.

   Evidence Isothermal titration calorimetry and CaV1.3 channel regulation assays comparing wild-type and truncated CaBP2 from a DFNB93 family

   PMID:22981119

   Open questions at the time

   • Did not define which structural region of CaBP2 contacts CaV1.3
   • Channel regulation assessed in vitro, not in native hair cells
2. 2016 Medium

   Demonstrated that CaBP2 is required for proper presynaptic Ca2+-dependent transmission of light responses in the retina, distinguishing a functional role from a structural one.

   Evidence Whole-cell patch clamp of retinal ganglion cells plus immunohistochemistry and electron microscopy in Cabp2 KO mice

   PMID:27822497

   Open questions at the time

   • Did not identify the specific channel CaBP2 modulates in retinal neurons
   • Mechanism of altered response kinetics not resolved at the molecular level
3. 2018 Medium

   Showed CaBP2 is required for normal peripheral auditory function across both inner and outer hair cell-dependent measures, defining the in vivo deafness phenotype.

   Evidence Auditory brainstem responses and distortion product otoacoustic emissions in Cabp2 KO mice

   PMID:29661613

   Open questions at the time

   • DPOAE deficit implicates outer hair cells but the molecular basis there was not established
   • Frequency-specific vulnerability not mechanistically explained
4. 2021 High

   Established causality and therapeutic reversibility by showing AAV-delivered Cabp2 restores CaV1.3 channel availability and hearing in knockout mice.

   Evidence AAV2/1 and AAV-PHP.eB gene delivery in Cabp2 KO mice with IHC patch clamp and in vivo ABR readouts

   PMID:34489639

   Open questions at the time

   • Durability of rescue and human translatability not addressed
   • Did not resolve stoichiometry of CaBP2:CaV1.3 interaction
5. 2025 Medium

   Consolidated the mechanistic model that CaBP2 suppresses CaV1.3 steady-state inactivation to maintain presynaptic Ca2+ channel availability for fatigue-resistant sound encoding.

   Evidence Review synthesizing DFNB93 mouse electrophysiology and gene therapy preclinical data

   PMID:40927552

   Open questions at the time

   • No new primary data
   • Structural basis of channel modulation still undefined

• The structural mechanism by which CaBP2 binds and modulates CaV1.3, and whether it acts on additional channel targets in retinal neurons, remains unresolved.
• No structure of a CaBP2–CaV1.3 complex
• Identity of the retinal channel target not established
• Interactome beyond CaV1.3 uncharacterized in the available corpus