SLC8B1 (solute carrier family 8 member B1), also known as SLC24A6, mitochondrial Na+/Ca2+ exchange protein 6 (NCKX6), is encoded by SLC8B1 gene in human. SLC8B1 belongs to SLC24A subfamily, a family of K+-dependent Na+/Ca2+ exchangers that utilize the extracellular sodium gradient to drive Ca2+ and K+ co-transport out of the cell to maintain cellular Ca2+ homeostasis. Containing 16 exons, SLC8B1 gene is located on chromosome 12q24.13. SLC8B1 is believed to share a common topology with other members of SLC24 family, and its 13 transmembrane helices (13TM) are divided into two conserved clusters by a divergent cytoplasmic loop. There are 1 potential cleavage site for signal peptidase and 2 N-glycosylation sites on the extracellular loop between TM1 and TM2, and 2 putative phosphorylation sites in the large intracellular loop between the TM6 and TM7.
|Basic Information of SLC8B1|
|Protein Name||Mitochondrial sodium/calcium exchanger protein|
|Aliases||NCKX6, NCLX, SLC24A6|
|Organism||Homo sapiens (Human)|
SLC8B1 (NCKX6) belongs to the NCKX transporters family which plays critical roles in retinal rod and cone photoreceptors, olfactory neurons, epidermal melanocytes, and the retinal pigment epithelium. As a mitochondrial Na+/Ca2+ antiporter, SLC8B1 is localized on the inner mitochondria membrane and mediates Na+ and K+-dependent Ca2+ efflux from the mitochondrion, which is essential for Ca2+ homeostasis, mitochondrial function and cell survival in diverse tissues and cell types, notably in cardiomyocytes, retinal rod and cone photoreceptors. Usually, it is changeless that the electrogenic countertransport of Na+/Ca2+/K+ is 4:1:1 ratio. The tamoxifen-induced deletion of SLC8B1 in murine hearts causes mitochondrial calcium overload, increases the generation of superoxide and necrotic cell death, and then leads to severe myocardial dysfunction and fulminant heart failure and ultimate sudden death. Moreover, SLC8B1 contributes to the regulation of glucose-dependent insulin secretion in pancreatic β-cells by mediating Ca2+ efflux from the mitochondrion, thereby affecting cytoplasmic calcium responses. It is documented that Na+ transport conducted by SLC8B1 can promote calcium-shuttling which modulates mitochondrial redox status, thereby regulating store-operated Ca2+ entry (SOCE) activity. SLC8B1 mediates the mitochondrial Na+ influx and plays a key role in the tetrodotoxin (TTX)-sensitive cytosolic Na+ responses.
Fig.1 Topology model for NCKX. (Lytton. 2007)
The authors investigated the potential roles of SLC24A6 in brain damage after intracerebral hemorrhage (ICH). They found that SLC24A6 was remarkably decreased in the early stage after ICH, along with a comparable increase in [Ca(2+)] concentration, indicating SLC24A6-mediated calcium overload may play an important role in brain damage after ICH.
This article summarized the current knowledge of NCKXs transports (K+-dependent Na+-Ca2+ exchangers) function. They described the NCKX1 transport function in the outer segments of retinal rod photoreceptors and elucidated structure-function relationships for the NCKX2 isoform.
The authors identified new mutations of SLC24A4 (NCKX4) in amylogenesis imperfecta (AI) and non-syndromic oculocutaneous albinism (OCA6) patients, supporting the genetic analyses that mutations in SLC24A4 and SLC24A5 were responsible for the phenotypic defects in human patients. They also studied NCKX-mediated Ca2+ transport activity of these mutants in HEK293 cells.
The authors revealed that the increase of extramitochondrial Na+ concentration can activate the Na+-Ca2+ exchange, thereby decreasing the matrix free [Ca2+] in a concentration-dependent manner. The high Na+ concentration also inhibited both the rate of NADH production and oxidative phosphorylation rate (OPR).
This review summarized the functions of three members in the NCKX (Na+-Ca2+-K+ exchanger) (SLC24) family. Depending on expression sites, NCKX may serve as a variety of roles, prominent in regulating Ca2+ flux in environments.
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