The SLC37 family of phosphate-linked sugar phosphate antiporters

Abstract

The SLC37 family consists of four sugar-phosphate exchangers, A1, A2, A3, and A4, which are anchored in the endoplasmic reticulum (ER) membrane. The best characterized family member is SLC37A4, better known as the glucose-6-phosphate (G6P) transporter (G6PT). SLC37A1, SLC37A2, and G6PT function as phosphate (Pi)-linked G6P antiporters catalyzing G6P:Pi and Pi:Pi exchanges. The activity of SLC37A3 is unknown. G6PT translocates G6P from the cytoplasm into the lumen of the ER where it couples with either glucose-6-phosphatase-α (G6Pase-α) or G6Pase-β to hydrolyze intraluminal G6P to glucose and Pi. The functional coupling of G6PT with G6Pase-α maintains interprandial glucose homeostasis and the functional coupling of G6PT with G6Pase-β maintains neutrophil energy homeostasis and functionality. A deficiency in G6PT causes glycogen storage disease type Ib, an autosomal recessive disorder characterized by impaired glucose homeostasis, neutropenia, and neutrophil dysfunction. Neither SLC37A1 nor SLC37A2 can functionally couple with G6Pase-α or G6Pase-β, and there are no known disease associations for them or SLC37A3. Since only G6PT matches the characteristics of the physiological ER G6P transporter involved in blood glucose homeostasis and neutrophil energy metabolism, the biological roles for the other SLC37 proteins remain to be determined.

Fig.1

The topology of G6PT and its functional coupling with G6Pase within the ER. The diagram shows a cross-section of the ER within two different cell types. The cell cytoplasm lies outside the ER membrane that encircles the ER lumen. In the gluconeogenic tissues of the liver, kidney and intestine, G6PT couples with G6Pase-α, while in neutrophils, G6PT couples with G6Pase-β. The proteins are shown as spatially separated for clarity, but evidence suggests that they reside in physical contact with each other as a G6PT/G6Pase complex. The G6PT/G6Pase-α complex expressed in gluconeogenic tissues maintains interprandial blood glucose homeostasis and disruption of either protein leads to the phenotype associated with impaired glucose homeostasis listed. The G6PT/G6Pase-β complex, which is ubiquitously expressed, is critical for maintaining neutrophil energy homeostasis and functionality, and disruption of either protein leads to neutropenia and the neutrophil dysfunctions listed.

Fig. 2

The antiporter activities of the SLC37 members. The antiporter activity was determined in 50 mM P_i -loaded proteoliposomes expressing SLC37A1, SLC37A2, SLC37A3, or G6PT. (A) G6P or P_i uptake activity. (B) Effects of chlorogenic acid. Data are presented as the mean ± SEM.

Fig. 3

Microsomal G6P transport activity of the SLC37 members. (A) Effects of G6Pase-α and G6Pase-β. G6P uptake activity was determined in microsomal membranes expressing SLC37A1, SLC37A2, or G6PT in the absence or presence of G6Pase-α or G6Pase-β. (B) G6P uptake activity in hepatic microsomes isolated from wild type (+/+), GSD-Ia (-/-) or Ad-G6Pase-α-treated GSD-Ia (Ad-G6Pase-α) mice. Data are presented as the mean ± SEM.

Fig. 4

The mRNA levels of the SLC37 members, relative to Slc37a4, in mouse liver, kidney, intestine, pancreas, neutrophils, and macrophages. The expression levels of the Slc37a1, Slc37a2, Slc37a3, and Slc37a4 transcripts were normalized to β-actin RNA and then scaled, for each tissue, relative to the Slc37a4 transcript which was arbitrarily assigned as 100%. Results are expressed as mean ± SEM.