SLC12A2 Membrane Protein Introduction

Introduction of SLC12A2

SLC12A2 (NKCC1) is widely distributed throughout the body, especially in organs that secrete fluids, called exocrine glands. In cells of these organs, SLC12A2 is commonly found in the basolateral membrane, the part of the cell membrane closest to the blood vessels. Its basolateral location gives SLC12A2 the ability to transport sodium, potassium, and chloride from the blood into the cell. The SLC12A2 soluted from the blood, particularly chloride, are secreted into the lumen of these exocrine glands, which can increase the luminal concentration of solutes and cause water to be secreted by osmosis.

Function of SLC12A2 Membrane Protein

SLC12A2 is necessary to establish the potassium-rich endolymph that bathes part of the cochlea, an organ necessary for hearing. Inhibition of SLC12A2, as with furosemide or other loop diuretics, can result in deafness. SLC12A2 is also expressed in many regions of the brain during early development, but not in adulthood. The change of SLC12A2 presence seems to be responsible for altering responses to the neurotransmitters GABA and glycine from excitatory to inhibitory, which was suggested to be important for early neuronal development. As long as SLC12A2 transporters are predominantly active, internal chloride concentrations in neurons are raised in comparison with mature chloride concentrations, which is important for GABA and glycine responses, as respective ligand-gated anion channels are permeable to chloride. With higher internal chloride concentrations, the outward driving force for this ion increases, and thus channel opening leads to chloride leaving the cell, thereby depolarizing it. Put another way, increasing internal chloride concentration increases the reversal potential for chloride, given by the Nernst equation. Later in development expression of SLC12A2 is reduced, while the expression of a KCC2 K-Cl cotransporter increased, thus bringing internal chloride concentration in neurons down to adult values.

Fig.1 The functions of NKCC1. (Buqing, 2017)

Application of SLC12A2 Membrane Protein in Literature

1. Ando Z., et al. Slc12a2 is a direct target of two closely related homeobox proteins, Six1 and Six4. FEBS J. 2005, 272(12):3026-41. PubMed ID: 15955062
   
   

   This article suggests that the promoter region of one of the targets, sodium-potassium-chloride cotransporter 1 (Slc12a2), contains multiple Six1-binding sites and one common binding site of Six1 and Six4, which means that the DNA-binding specificity of Six1 is distinct from that of Six4. This underlies the differential regulation of common target genes by Six1 and Six4. In situ hybridization demonstrates that the expression of Slc12a2 is reduced in the developing dorsal root ganglia of Six1^-/-/Six4^-/- mice.

2. Abbas L. and Whitfield T.T. Novel SLC12A1 (NKCC2) mutations in two families with Bartter syndrome type 1. Development. 2009, 136(16):2837-48. PubMed ID: 19633174
   
   

   The article shows that each allele has a point mutation that disrupts splicing, leading to frame shifts in the coding region that predict the generation of truncated products. It exemplifies the use of morpholinos as potential therapeutic agents for genetic disease.

3. Callicott J.H., et al. DISC1 and SLC12A2 interaction affects human hippocampal function and connectivity. J Clin Invest. 2013, 123(7):2961-4. PubMed ID: 23921125
   
   

   The previous study has reported that SLC12A2-dependent GABA depolarization and DISC1 coregulate hippocampal neuronal development, and 2 SNPs in these genes linked to mRNA expression interactively increase schizophrenia risk. This article confirmed that this biological interaction in vivo, evince dramatically decreased hippocampal area activation and connectivity during a recognition memory task. It highlights the importance of epistatic models in understanding the genetic association with complex brain phenotypes.

4. Merner N.D., e al. Gain-of-function missense variant in SLC12A2, encoding the bumetanide-sensitive NKCC1 cotransporter, identified in human schizophrenia. J Psychiatr Res. 2016, 77:22-6. PubMed ID: 26955005
   
   

   In this study, authors describe a functional missense variant in SLC12A2 in human schizophrenia and suggest that genetically encoded dysregulation of NKCC1 may be a risk factor for, or contribute to the pathogenesis of, human schizophrenia.

5. Walters Z.S., et al. NKCC1 (SLC12a2) induces a secondary axis in Xenopus laevis embryos independently of its co-transporter function. J Physiol. 2009, 587(3):521-9. PubMed ID: 19047208
   
   

   In this report, they show that overexpression of NKCC1 in embryos of Xenopus laevis induces secondary axes, independently of its co-transporter activity. In addition, overexpression of NKCC1 results in the formation of neural tissue in ectodermal explants. They also show that NKCC1 is expressed broadly but non-uniformly in embryos of Xenopus laevis and Xenopus tropicalis, with prominent expression in the notochord, nervous system and stomach. These results provide insights into an additional, previously unreported activity of NKCCl.

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Reference

1. Liang B and Huang J H. (2017). Elevated NKCC1 transporter expression facilitates early post-traumatic brain injury seizures. Neural Regen Res. 12(3), 401-402.

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