9dyl

Structural highlights

Disease

BEST1_HUMAN MRCS syndrome;Adult-onset foveomacular vitelliform dystrophy;Retinitis pigmentosa;Autosomal dominant vitreoretinochoroidopathy;Nanophthalmos;Best vitelliform macular dystrophy;Autosomal recessive bestrophinopathy. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

BEST1_HUMAN Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+) (PubMed:11904445, PubMed:12907679, PubMed:18179881, PubMed:18400985, PubMed:19853238, PubMed:21330666, PubMed:26200502, PubMed:26720466, PubMed:35789156). Allows the movement of chloride and hydrogencarbonate (PubMed:11904445, PubMed:12907679, PubMed:18179881, PubMed:18400985, PubMed:19853238, PubMed:21330666, PubMed:26200502, PubMed:26720466, PubMed:35789156). Found in a partially open conformation leading to significantly smaller chloride movement (PubMed:35789156). Upon F2R/PAR-1 activation, the sequestered calcium is released into the cytosol of astrocytes, leading to the (Ca2+)-dependent release of L-glutamate into the synaptic cleft that targets the neuronal postsynaptic GRIN2A/NMDAR receptor resulting in the synaptic plasticity regulation (By similarity). Upon activation of the norepinephrine-alpha-1 adrenergic receptor signaling pathway, transports as well D-serine than L-glutamate in a (Ca2+)-dependent manner, leading to activation of adjacent NMDAR receptors and therefore regulates the heterosynaptic long-term depression and metaplasticity during initial memory acquisition (By similarity). Releases the 4-aminobutanoate neurotransmitter in a (Ca2+)-dependent manner, and participates in its tonic release from cerebellar glial cells (By similarity).[UniProtKB:O88870]^{[1] [2] [3] [4] [5] [6] [7] [8] [9]}

References

1. ↑ Sun H, Tsunenari T, Yau KW, Nathans J. The vitelliform macular dystrophy protein defines a new family of chloride channels. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):4008-13. doi: 10.1073/pnas.052692999. PMID:11904445 doi:http://dx.doi.org/10.1073/pnas.052692999
2. ↑ Tsunenari T, Sun H, Williams J, Cahill H, Smallwood P, Yau KW, Nathans J. Structure-function analysis of the bestrophin family of anion channels. J Biol Chem. 2003 Oct 17;278(42):41114-25. doi: 10.1074/jbc.M306150200. Epub 2003, Aug 7. PMID:12907679 doi:http://dx.doi.org/10.1074/jbc.M306150200
3. ↑ Burgess R, Millar ID, Leroy BP, Urquhart JE, Fearon IM, De Baere E, Brown PD, Robson AG, Wright GA, Kestelyn P, Holder GE, Webster AR, Manson FD, Black GC. Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am J Hum Genet. 2008 Jan;82(1):19-31. PMID:18179881 doi:10.1016/j.ajhg.2007.08.004
4. ↑ Qu Z, Hartzell HC. Bestrophin Cl- channels are highly permeable to HCO3-. Am J Physiol Cell Physiol. 2008 Jun;294(6):C1371-7. doi:, 10.1152/ajpcell.00398.2007. Epub 2008 Apr 9. PMID:18400985 doi:http://dx.doi.org/10.1152/ajpcell.00398.2007
5. ↑ Davidson AE, Millar ID, Urquhart JE, Burgess-Mullan R, Shweikh Y, Parry N, O'Sullivan J, Maher GJ, McKibbin M, Downes SM, Lotery AJ, Jacobson SG, Brown PD, Black GC, Manson FD. Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa. Am J Hum Genet. 2009 Nov;85(5):581-92. PMID:19853238 doi:10.1016/j.ajhg.2009.09.015
6. ↑ Davidson AE, Millar ID, Burgess-Mullan R, Maher GJ, Urquhart JE, Brown PD, Black GC, Manson FD. Functional characterization of bestrophin-1 missense mutations associated with autosomal recessive bestrophinopathy. Invest Ophthalmol Vis Sci. 2011 Jun 1;52(6):3730-6. PMID:21330666 doi:10.1167/iovs.10-6707
7. ↑ Johnson AA, Bachman LA, Gilles BJ, Cross SD, Stelzig KE, Resch ZT, Marmorstein LY, Pulido JS, Marmorstein AD. Autosomal Recessive Bestrophinopathy Is Not Associated With the Loss of Bestrophin-1 Anion Channel Function in a Patient With a Novel BEST1 Mutation. Invest Ophthalmol Vis Sci. 2015 Jul;56(8):4619-30. PMID:26200502 doi:10.1167/iovs.15-16910
8. ↑ Lee CS, Jun I, Choi SI, Lee JH, Lee MG, Lee SC, Kim EK. A Novel BEST1 Mutation in Autosomal Recessive Bestrophinopathy. Invest Ophthalmol Vis Sci. 2015 Dec;56(13):8141-50. PMID:26720466 doi:10.1167/iovs.15-18168
9. ↑ Owji AP, Wang J, Kittredge A, Clark Z, Zhang Y, Hendrickson WA, Yang T. Structures and gating mechanisms of human bestrophin anion channels. Nat Commun. 2022 Jul 4;13(1):3836. PMID:35789156 doi:10.1038/s41467-022-31437-7
10. ↑ Owji AP, Dong J, Kittredge A, Wang J, Zhang Y, Yang T. Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment. Nat Commun. 2024 Dec 30;15(1):10766. PMID:39737942 doi:10.1038/s41467-024-54938-z