The betaine/GABA transporter and betaine: roles in brain, kidney, and liver

Abstract

The physiological roles of the betaine/GABA transporter (BGT1; slc6a12) are still being debated. BGT1 is a member of the solute carrier family 6 (the neurotransmitter, sodium symporter transporter family) and mediates cellular uptake of betaine and GABA in a sodium- and chloride-dependent process. Most of the studies of BGT1 concern its function and regulation in the kidney medulla where its role is best understood. The conditions here are hostile due to hyperosmolarity and significant concentrations of NH4Cl and urea. To withstand the hyperosmolarity, cells trigger osmotic adaptation, involving concentration of a transcriptional factor TonEBP/NFAT5 in the nucleus, and accumulate betaine and other osmolytes. Data from renal cells in culture, primarily MDCK, revealed that transcriptional regulation of BGT1 by TonEBP/NFAT5 is relatively slow. To allow more acute control of the abundance of BGT1 protein in the plasma membrane, there is also post-translation regulation of BGT1 protein trafficking which is dependent on intracellular calcium and ATP. Further, betaine may be important in liver metabolism as a methyl donor. In fact, in the mouse the liver is the organ with the highest content of BGT1. Hepatocytes express high levels of both BGT1 and the only enzyme that can metabolize betaine, namely betaine:homocysteine -S-methyltransferase (BHMT1). The BHMT1 enzyme removes a methyl group from betaine and transfers it to homocysteine, a potential risk factor for cardiovascular disease. Finally, BGT1 has been proposed to play a role in controlling brain excitability and thereby represents a target for anticonvulsive drug development. The latter hypothesis is controversial due to very low expression levels of BGT1 relative to other GABA transporters in brain, and also the primary location of BGT1 at the surface of the brain in the leptomeninges. These issues are discussed in detail.

Keywords: hepatocytes; leptomeninges; methyl donor; mouse models; osmolyte; renal medulla; synapse.

Figure 1

BGT1 is expressed in the leptomeninges. The sections from wildtype and knockout were labeled with anti-BGT1 antibody (red; Ab#590; 1 μg/ml), and with anti-CD31 antibodies (green; 0.5 μg/ml; endothelial marker). The images from the sections from knockout mice are not shown here. Scale bars = 20 μm. Immunochemistry was performed using the same materials and procedures described in detail by Zhou et al. (2012a).

Figure 2

BGT1 localization in the kidney. The kidney sections from wildtype and knockout were labeled with anti-BGT1 antibody (red; Ab#590; 1 μg/ml), and with fluorescein-conjugated D. biflorus agglutinin (green; 1:300; marker for collecting ducts). (A,B) are from the outer strip of outer medulla, and (C,D) are from the tip of the renal papilla. The images from the sections from knockout mice are not shown here. Scale bars for (A,C) = 50 μm; scale bars for (B,D) = 20 μm. Immunochemistry was performed using the same materials and procedures described in detail by Zhou et al. (2012a).

Figure 3

Schematic illustration of the distributions of TonEBP, BGT1, AR, SMIT1, and TAUT as well as the related osmolytes in the kidney. TonEBP is present in most tubular profiles in the medulla, including the loop of Henle and medullary collecting ducts and interstitial cells (Han et al., 2004). BGT1 is present in the medullary thick ascending limbs of Henle loop and the medullary collecting ducts (Miyai et al., ; Zhou et al., 2012a). Aldose reductase (AR) is in the loop of Henle and inner medullary collecting ducts (Terubayashi et al., ; Schwartz et al., ; Grunewald et al., 2001). SMIT1 is predominantly present in the medullary and cortical thick ascending limb of Henle's loop and in the cells of the macula densa as well as to a lesser extent in the inner medullary collecting ducts (Yamauchi et al., 1995). TAUT is localized to the proximal tubules in the outer stripe of outer medulla (Park et al., ; Lopez-Rodriguez et al., 2004). Organic osmolytes including betaine and sorbitol exhibit their highest concentrations in the papillary tip, except myo-inositol which has similar high concentrations in inner and outer medulla (Wirthensohn et al., ; Yancey and Burg, 1989).

Figure 4

Role of betaine in the methionine cycle in liver. Betaine provides an alternative pathway for methylation of homocysteine. BHMT, betaine-homocysteine S-methyltransferase. MS, methionine synthase. Modified from Craig (2004).

Figure 5

BGT1 localization in the liver. The section was double labeled with anti-CD31 antibodies (green; 0.5 μg/ml; endothelial marker) and anti-BGT1 antibodies (red; Ab#594; 1 μg/ml). Scale bars = 20 μm. Immunochemistry was performed using the same materials and procedures described in detail by Zhou et al. (2012a).