Alternative titles; symbols
HGNC Approved Gene Symbol: CABP1
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38) : 12:120,640,626-120,680,866 (from NCBI)
Calcium ion is a universally employed cytosolic messenger in eukaryotic cells and is involved in many cellular processes, such as signal transduction, contraction, secretion, and cell proliferation. The effects of Ca(2+) are mediated by calcium-binding proteins, including the EF-hand protein family, whose members are characterized by single or multiple pairs of a common helix-loop-helix motif that coordinates Ca(2+) (summary by Yamaguchi et al., 1999).
Yamaguchi et al. (1999) isolated a human brain cDNA clone encoding a novel calcium-binding protein, CABP1, which they termed calbrain. The protein contains 70 amino acids and has a predicted molecular mass of 8.06 kD. Sequence analysis showed that CABP1 contains 2 putative EF-hand motifs that show significant homology to those of the calmodulin family (see 114180) rather than those of 2-EF-hand protein families. Northern blot analysis revealed brain-restricted expression of an approximately 1.5-kb CABP1 transcript. In situ hybridization analysis showed abundant expression in the hippocampus, the habenular nucleus of the epithalamus, and the Purkinje cell layer of the cerebellum.
By searching an EST database using the Ca(2+)-binding loops of GCAP1 (600364) as the query, followed by nested PCR of a retina cDNA library, Haeseleer et al. (2000) cloned a full-length cDNA encoding CABP1. The deduced 227-amino acid protein has a calculated molecular mass of about 26 kD and contains a putative N-terminal myristoylation site and 3 putative functional EF-hands that correspond to EF-hands 1, 3, and 4 of calmodulin. Changes within the EF-hand 2 motif of CABP1 may not allow Ca(2+) coordination. Haeseleer et al. (2000) also cloned a short CABP1 variant that encodes a deduced 167-amino acid protein with a calculated molecular mass of about 19.4 kD. The short isoform retains the 15 N-terminal amino acids, including the N-myristoylation site, and the C-terminal ER-hand motifs of full-length CABP1, but it lacks 60 intervening amino acids. Full-length CABP1 shares about 96% similarity with its bovine and mouse homologs and about 56% similarity with calmodulin. Northern blot analysis detected a transcript of 1.7 kb in bovine retina and human brain. By RT-PCR, CABP1 was detected in mouse retina and cerebellum. Immunolocalization of Cabp1 in mouse retina indicated expression restricted to amacrine cells and cone bipolar cells. Confocal microscopy indicated that the intracellular localization of the CABP1 splice variants differed upon transfection and expression in CHO cells, with the shorter form localized at or near the plasma membrane, and the long form associated with cytoskeletal structures.
Using a master RNA blot, Sokal et al. (2000) detected CABP1 expression in whole brain, occipital lobe, and cerebral cortex. Much lower levels were detected in frontal lobe, hippocampus, temporal lobe, and nucleus accumbeus. RT-PCR revealed CABP1 expression in retina and cerebellum.
Tippens and Lee (2007) stated that the caldendrin splice variant of rat Cabp1 encodes an isoform identical to full-length Cabp1 in its C-terminal half, but that it has a unique N-terminal half that lacks the N-myristoylation site.
Using immunohistochemical analysis, Cui et al. (2007) found that Cabp1 localized strongly at presynaptic ribbon synapses of mouse organ of Corti.
Using in vitro studies, Yamaguchi et al. (1999) found that CABP1 competitively inhibits calmodulin binding to Ca(2+)/calmodulin-dependent kinase II (CAMK2; see 114078), the most abundant protein kinase in the hippocampus, which is strongly implicated in basic neuronal functions, and reduced its kinase activity and autophosphorylation. The authors suggested that CABP1 may be involved in neuronal signal transduction and memory.
Haeseleer et al. (2000) found that CABP1 is myristoylated in vitro. In contrast to the findings of Yamaguchi et al. (1999), they determined that the short form of CABP1, purified from bovine retina, stimulated CAMK2 in the presence of Ca(2+). They suggested that the inhibition measured by Yamaguchi et al. (1999) may have been due to the fact that calbrain represents only a partial clone of CABP1. CABP1 also showed high-affinity binding with G protein-coupled receptor kinase-5 (GRK5; 600870), and it inhibited GRK5-mediated phosphorylation of rhodopsin (180380).
Using in vitro assays, Lee et al. (2002) found that CABP1 modulates the activity of a rat P/Q-type voltage-dependent Ca(2+) channel through interaction with the alpha-1 subunit (CACNA1A; 601011). CABP1 enhanced inactivation, caused a depolarizing shift in the voltage dependence of activation, and did not support Ca(2+)-dependent facilitation of the channel. The inhibitory effects of CABP1 did not require Ca(2+), but depended on the calmodulin-binding domain within Cacna1a. Through yeast 2-hybrid screens and coimmunoprecipitation of transfected cells or rat brain cytosol, Lee et al. (2002) demonstrated direct interaction between CABP1 and Cacna1a. The 2 proteins also colocalized in discrete microdomains of neurons in rat hippocampus and cerebellum.
Tippens and Lee (2007) stated that the full-length variant of rat Cabp1 accelerates inactivation of Cav2.1 (P/Q-type) channels independent of Ca(2+), and that it stabilizes channel opening for Cav1.2 (L-type) channels (CACNA1C; 114205) by suppressing Ca(2+)-dependent channel inactivation. They found that the rat caldendrin isoform functioned differently than full-length Cabp1 in modulating Cav1.2 calcium currents. Caldendrin bound the C-terminal IQ domain of Cav1.2 and competitively displaced calmodulin and Cabp1 in a Ca(2+)-independent manner. Compared with full-length Cabp1, caldendrin had a more modest effect in suppressing Ca(2+)-dependent inactivation of Cav1.2, possibly due to the inability of caldendrin to bind the N-terminal domain of Cav1.2. Caldendrin coimmunoprecipitated with Cav1.2 from rat brain and colocalized with Cav1.2 in somatodendritic puncta of rat cortical neurons in culture.
Cav1.3 voltage-gated Ca(2+) channels (CACNA1D; 114206) of rodent auditory inner hair cells show little Ca(2+)-dependent inactivation, which involves association of calmodulin with the channel alpha-1 subunit. Using transfected HEK293 cells, Cui et al. (2007) found that human CABP1 blunted Ca(2+)-dependent inactivation of rat Cav1.3 more efficiently than other CABPs tested, suggesting that CABP1 may modulate Cav1.3 channels in inner hair cells.
Haeseleer et al. (2000) determined that the CABP1 gene contains 6 exons and spans about 16 kb. Compared with the calmodulin gene, it has an additional exon, termed exon 2A.
By genomic sequence analysis, Haeseleer et al. (2000) mapped the CABP1 gene to chromosome 12.
Cui, G., Meyer, A. C., Calin-Jagerman, I., Neef, J., Haeseleer, F., Moser, T., Lee, A. Ca(2+)-binding proteins tune Ca(2+)-feedback to Cav1.3 channels in mouse auditory hair cells. J. Physiol. 585: 791-803, 2007. [PubMed: 17947313] [Full Text: https://doi.org/10.1113/jphysiol.2007.142307]
Haeseleer, F., Sokal, I., Verlinde, C. L. M. J., Erdjument-Bromage, H., Tempst, P., Pronin, A. N., Benovic, J. L., Fariss, R. N., Palczewski, K. Five members of a novel Ca(2+)-binding protein (CABP) subfamily with similarity to calmodulin. J. Biol. Chem. 275: 1247-1260, 2000. [PubMed: 10625670] [Full Text: https://doi.org/10.1074/jbc.275.2.1247]
Lee, A., Westenbroek, R. E., Haeseleer, F., Palczewski, K., Scheuer, T., Catterall, W. A. Differential modulation of Ca(V)2.1 channels by calmodulin and Ca(2+)-binding protein 1. Nature Neurosci. 5: 210-217, 2002. [PubMed: 11865310] [Full Text: https://doi.org/10.1038/nn805]
Sokal, I., Li, N., Verlinde, C. L. M. J., Haeseleer, F., Baehr, W., Palczewski, K. Ca(2+)-binding proteins in the retina: from discovery to etiology of human disease. Biochim. Biophys. Acta 1498: 233-251, 2000. [PubMed: 11108966] [Full Text: https://doi.org/10.1016/s0167-4889(00)00099-9]
Tippens, A. L., Lee, A. Caldendrin, a neuron-specific modulator of Cav1.2 (L-type) Ca(2+) channels. J. Biol. Chem. 282: 8464-8473, 2007. [PubMed: 17224447] [Full Text: https://doi.org/10.1074/jbc.M611384200]
Yamaguchi, K., Yamaguchi, F., Miyamoto, O., Sugimoto, K., Konishi, R., Hatase, O., Tokuda, M. Calbrain, a novel two EF-hand calcium-binding protein that suppresses Ca(2+)/calmodulin-dependent protein kinase II activity in the brain. J. Biol. Chem. 274: 3610-3616, 1999. [PubMed: 9920909] [Full Text: https://doi.org/10.1074/jbc.274.6.3610]