Alternative titles; symbols
HGNC Approved Gene Symbol: DBI
Cytogenetic location: 2q14.2 Genomic coordinates (GRCh38): 2:119,366,977-119,372,543 (from NCBI)
Benzodiazepines modulate signal transduction at type A GABA (gamma-aminobutyric acid) receptors (137160) located in brain synapses. GABA is the predominant inhibitory neurotransmitter of the mammalian central nervous system. This receptor binds GABA, beta-carbolines, and benzodiazepines with high affinity and a chloride ion channel. Benzodiazepines prolong the chloride ion channel opening burst elicited by GABA and thereby enhance GABA-mediated inhibitory responses. This facilitation plays a role in reducing pathologic anxiety. An endogenous ligand has been identified that is recognized by the beta-carboline/benzodiazepine recognition site located in the GABA receptor. This ligand, diazepam binding inhibitor (DBI), is a protein of about 11 kD that displaces beta-carbolines and benzodiazepines bound to brain membrane fractions in vitro. DBI or a derivative small neuropeptide is thought to downregulate the effects of GABA (summary by Gray et al., 1986).
Gray et al. (1986) isolated a cDNA clone that encodes human DBI. A polypeptide related to DBI, with similar binding activity to diazepam, has been isolated from human and bovine brain. This protein, called endozepine, contains 86 amino residues. Webb et al. (1987) cloned endozepine cDNAs from bovine and human libraries and found 93% homology in the coding regions of the bovine and human forms. The message is 650 nucleotides long. Northern analysis using the cloned cDNA demonstrated that the message is expressed in heart, liver, and spleen, in addition to brain.
Diazepam binding inhibitor is also known as acyl-CoA-binding protein (ACBP). Rose et al. (1992) cloned the homologous gene from the budding yeast Saccharomyces cerevisiae. The yeast gene contains no introns and encodes a polypeptide of 87 amino acids (including the initiating methionine), identical in length to the human gene product with 48% conservation of amino acid residues. The most highly conserved domain comprises 7 contiguous residues that are identical in all known protein species from yeast, birds, and mammals. This domain constitutes the hydrophobic binding site for acyl-CoA esters and is located within the second helical region of the molecule. The presence of a highly conserved gene in a primitive organism such as yeast supports its basic biologic role as an acyl-CoA-binding protein and suggests that many of the biologic functions attributed to it in higher organisms may result from its ability to interact with acyl-CoA. Rose et al. (1992) designated the yeast gene ACB, for acyl-CoA binding.
Benzodiazepine receptors unassociated with the GABA receptor complex, and distinct from those seen in association with the central nervous system, have been identified in peripheral tissues. Anholt et al. (1986) presented evidence that these peripheral receptors are localized on the mitochondrial outer membrane. Webb et al. (1987) speculated that the role of endozepine in peripheral tissues is to interact with this receptor.
Herzig et al. (1996) isolated a trypsin-sensitive cholecystokinin (CCK; 118440)-releasing peptide (CCK-RP) from porcine and rat intestinal mucosa. At the same time, Spannagel et al. (1996) purified a luminal CCK-releasing factor from rat intestinal secretions. Herzig et al. (1996) found that the amino acid sequence of CCK-RP was identical to that of diazepam-binding inhibitor. Li et al. (2000) demonstrated that DBI mediates the feedback regulation of pancreatic secretion and the postprandial release of cholecystokinin.
By in situ hybridization and Southern blot analysis of human-mouse hybrid cell lines, DeBernardi et al. (1988) mapped the DBI gene to 2q12-q21. By in situ hybridization, secondary signals were observed on other chromosomes, mainly nos. 5, 6, 11 and 14. The cell hybrid studies suggested that 3 homologous sequences are on other chromosomes.
Todd and Naylor (1992) used the nucleotide sequence of the DBI gene as recorded in the GenBank database to generate DNA primers to amplify specific sequences by PCR. The primers failed to amplify DNA sequences when used to analyze microcell hybrid clones containing human chromosome 2. Therefore, in order to map the gene, a panel of somatic cell hybrids was analyzed by PCR. The results of this experiment placed DBI on human chromosome 6. Hybrid cells contained the DBI gene only when the region 6q12-q21 was present.
Gersuk et al. (1995) cloned and sequenced a pseudogene of ACBP/DBI. The locus, called DIBP1, mapped to chromosome 6. The authors concluded that the functional gene must be located on chromosome 2.
Anholt, R. R. H., Pedersen, P. L., Desouza, E. B., Snyder, S. H. The peripheral-type benzodiazepine receptor: localization to the mitochondrial outer membrane. J. Biol. Chem. 261: 576-583, 1986. [PubMed: 3001071]
DeBernardi, M. A., Crowe, R. R., Mocchetti, I., Shows, T. B., Eddy, R. L., Costa, E. Chromosomal localization of the human diazepam binding inhibitor gene. Proc. Nat. Acad. Sci. 85: 6561-6565, 1988. [PubMed: 3413112] [Full Text: https://doi.org/10.1073/pnas.85.17.6561]
Gersuk, V. H., Rose, T. M., Todaro, G. J. Molecular cloning and chromosomal localization of a pseudogene related to the human acyl-CoA binding protein/diazepam binding inhibitor. Genomics 25: 469-476, 1995. [PubMed: 7789980] [Full Text: https://doi.org/10.1016/0888-7543(95)80047-p]
Gray, P. W., Glaister, D., Seeburg, P. H., Guidotti, A., Costa, E. Cloning and expression of cDNA for human diazepam binding inhibitor, a natural ligand of an allosteric regulatory site of the gamma-aminobutyric acid type A receptor. Proc. Nat. Acad. Sci. 83: 7547-7551, 1986. [PubMed: 3020548] [Full Text: https://doi.org/10.1073/pnas.83.19.7547]
Herzig, K. H., Schon, I., Tatemoto, K., Ohe, Y., Li, Y., Folsch, U. R., Owyang, C. Diazepam binding inhibitor is a potent cholecystokinin-releasing peptide in the intestine. Proc. Nat. Acad. Sci. 93: 7927-7932, 1996. Note: Erratum: Proc. Nat. Acad. Sci. 93: 14214 only, 1996. [PubMed: 8755579] [Full Text: https://doi.org/10.1073/pnas.93.15.7927]
Li, Y., Hao, Y., Owyang, C. Diazepam-binding inhibitor mediates feedback regulation of pancreatic secretion and postprandial release of cholecystokinin. J. Clin. Invest. 105: 351-359, 2000. [PubMed: 10675361] [Full Text: https://doi.org/10.1172/JCI7204]
Rose, T. M., Schultz, E. R., Todaro, G. J. Molecular cloning of the gene for the yeast homolog (ACB) of diazepam binding inhibitor/endozepine/acyl-CoA-binding protein. Proc. Nat. Acad. Sci. 89: 11287-11291, 1992. [PubMed: 1454809] [Full Text: https://doi.org/10.1073/pnas.89.23.11287]
Spannagel, A. W., Green, G. M., Guan, D., Liddle, R. A., Faull, K., Reeve, J. R. Purification and characterization of a luminal cholecystokinin-releasing factor from rat intestinal secretion. Proc. Nat. Acad. Sci. 93: 4415-4420, 1996. [PubMed: 8633081] [Full Text: https://doi.org/10.1073/pnas.93.9.4415]
Todd, S., Naylor, S. L. New chromosomal mapping assignments for argininosuccinate synthetase pseudogene 1, interferon-beta-3 gene, and the diazepam binding inhibitor gene. Somat. Cell Molec. Genet. 18: 381-385, 1992. [PubMed: 1440058] [Full Text: https://doi.org/10.1007/BF01235761]
Webb, N. R., Rose, T. M., Malik, N., Marquardt, H., Shoyab, M., Todaro, G. J., Lee, D. C. Bovine and human cDNA sequences encoding a putative benzodiazepine receptor ligand. DNA 6: 71-79, 1987. [PubMed: 2881742] [Full Text: https://doi.org/10.1089/dna.1987.6.71]