The small-intestinal Na+,d-glucose cotransporter: An asymmetric gated channel (or pore) responsive to ΔΨ

Kessler, Markus; Semenza, Giorgio

doi:10.1007/bf01871452

Cited by 118 publications

(82 citation statements)

References 75 publications

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“…The revised model also predicts an inhibition of forward Na + /glucose transport by internal Na + in the absence of internal glucose (trans-Na + inhibition) with a K 0.5 (57 mM at 0 V) that is similar to that reported by Kaunitz & Wright, 1984 (54 mM at 0 mV). There is a predicted inhibition of forward transport by internal glucose in the absence of internal Na + (trans-sugar inhibition) with a K 0.5 of 62 mM (at 0 mV) that is similar to that (≈50 mM at 0 mV) reported by Kessler & Semenza (1983). Thus, the revised model can predict: 1) the difference in the I/V relations between the forward and reverse modes; 2) the K 0.5 values for Na + and sugar for both forward and reverse modes; and 3) trans-inhibition of forward sugar transport by internal Na + and glucose.…”

Section: Discussionsupporting

confidence: 76%

Kinetics of the Reverse Mode of the Na+/Glucose Cotransporter

2005

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This study investigates the reverse mode of the Na + /glucose cotransporter (SGLT1). In giant excised inside-out membrane patches from Xenopus laevis oocytes expressing rabbit SGLT1, application of α-methyl-D-glucopyranoside (αMDG) to the cytoplasmic solution induced an outward current from cytosolic to external membrane surface. The outward current was Na + -and sugar-dependent, and was blocked by phlorizin, a specific inhibitor of SGLT1. The currentvoltage relationship saturated at positive membrane voltages (30-50 mV), and approached zero at − 150 mV. The half-maximal concentration for αMDG-evoked outward current ( ) was 35 mM (at 0 mV). In comparison, for forward sugar transport was 0.15 mM (at 0 mV). was similar for forward and reverse transport (≈35 mM at 0 mV). Specificity of SGLT1 for reverse transport was: αMDG (1.0) > D-galactose (0.84) > 3-O-methyl-glucose (0.55) > D-glucose (0.38), whereas for forward transport, specificity was: αMDG ≈ D-glucose ≈ D-galactose > 3-Omethyl-glucose. Thus there is an asymmetry in sugar kinetics and specificity between forward and reverse modes. Computer simulations showed that a 6-state kinetic model for SGLT1 can account for Na + /sugar cotransport and its voltage dependence in both the forward and reverse modes at saturating sodium concentrations. Our data indicate that under physiological conditions, the transporter is poised to accumulate sugar efficiently in the enterocyte.

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Section: Discussionsupporting

confidence: 76%

Kinetics of the Reverse Mode of the Na+/Glucose Cotransporter

2005

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“…In both control and ischemic BBMV, LAP was readily accessible to the antibody, and nearly complete neutralization of LAP activity was seen in both control and ischemic membrane vesicles. This is important, as recent evidence indicates the Na+-dependent glucose transporter may be asymmetric and an alteration in sidedness of the vesicle could therefore alter transport characteristics (26). This, however, did not seem to be the case after reversible ischemic injury.…”

Section: Discussionmentioning

confidence: 94%

“…As the Na+-dependent glucose transporter may be located asymmetrically in apical membranes (26); an alteration in sid- and ischemic (o) BBMV. Transport buffers were described in Fig.…”

Section: Resultsmentioning

confidence: 99%

Ischemia induces surface membrane dysfunction. Mechanism of altered Na+-dependent glucose transport.

Molitoris¹,

Kinne²

1987

J. Clin. Invest.

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Reversible ischemia reduced renal cortical brush border membrane (BBM) Na'-dependent D-glucose uptake (336±31 vs.138±30 pmol/mg per 2 s, P < 0.01) but had-no effect on Na'-independent glucose or Na'-dependent L-alanine uptake.The effect on D-glucose uptake was present after only 15 mm of ischemia and was due to a reduction in maximum velocity (1913±251 vs. 999±130 pmol/mg per 2 s; P < 0.01). This reduction was not due to more rapid dissipation of the Na' gradient, altered sidedness of the vesicles, or an alteration in membrane potential. Ischemia did, however, reduce the BBM sphingomyelin-to-phosphatidylcholine (SPH/PC) and cholesterol-to-phospholipid ratios and the number of specific highaffinity Na'-dependent phlorizin binding sites (390±43 vs.146±24 pmol/mg; P < 0.01) without altering the binding dissociation constant (Kd). 20 mM benzyl alcohol also reduced the number of Na'-dependent phlorizin binding sites (418±65 vs. 117±46; P < 0.01) without altering Kd. The reduction in Na+-dependent D-glucose transport correlated with ischemic-induced changes in the BBM SPH/PC and cholesterol-to-phospholipid ratios and membrane fluidity. Taken together these data indicate the cellular site responsible for ischemic-induced reduction in renal cortical transcellular glucose transport is the BBM. We propose the mechanism involves marked alterations in BBM lipids leading to large increases in BBM fluidity which reduces the binding capacity of Na'-dependent glucose carriers. These data indicate that reversible ischemia has profound effects on the surface membrane function of epithelial cells.

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“…From the work done by Wright and others the kinetics and rate of SGLT1 transport is well known (37,64,65,97). The saturated stoichiometry of the SGLT1 cotransporter is two Na ϩ ions for each glucose molecule (31,64).…”

Section: Sglt1mentioning

confidence: 99%

Transepithelial glucose transport and Na⁺/K⁺ homeostasis in enterocytes: an integrative model

Thorsen

Drengstig

Ruoff

2014

American Journal of Physiology-Cell Physiology

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Thorsen K, Drengstig T, Ruoff P. Transepithelial glucose transport and Na ϩ /K ϩ homeostasis in enterocytes: an integrative model. Am J Physiol Cell Physiol 307: C320 -C337, 2014. First published June 4, 2014; doi:10.1152/ajpcell.00068.2013.-The uptake of glucose and the nutrient coupled transcellular sodium traffic across epithelial cells in the small intestine has been an ongoing topic in physiological research for over half a century. Driving the uptake of nutrients like glucose, enterocytes must have regulatory mechanisms that respond to the considerable changes in the inflow of sodium during absorption. The Na-K-ATPase membrane protein plays a major role in this regulation. We propose the hypothesis that the amount of active Na-K-ATPase in enterocytes is directly regulated by the concentration of intracellular Na ϩ and that this regulation together with a regulation of basolateral K permeability by intracellular ATP gives the enterocyte the ability to maintain ionic Na ϩ /K ϩ homeostasis. To explore these regulatory mechanisms, we present a mathematical model of the sodium coupled uptake of glucose in epithelial enterocytes. Our model integrates knowledge about individual transporter proteins including apical SGLT1, basolateral Na-K-ATPase, and GLUT2, together with diffusion and membrane potentials. The intracellular concentrations of glucose, sodium, potassium, and chloride are modeled by nonlinear differential equations, and molecular flows are calculated based on experimental kinetic data from the literature, including substrate saturation, product inhibition, and modulation by membrane potential. Simulation results of the model without the addition of regulatory mechanisms fit well with published short-term observations, including cell depolarization and increased concentration of intracellular glucose and sodium during increased concentration of luminal glucose/sodium. Adding regulatory mechanisms for regulation of Na-K-ATPase and K permeability to the model show that our hypothesis predicts observed long-term ionic homeostasis.enterocytes; epithelial transport; homeostasis; mathematical modeling; ionic regulation THE UPTAKE AND TRANSPORT OF glucose by the epithelial enterocytes in the small intestine are essential steps in all higher animals. Much of the glucose uptake in the small intestine is coupled to transport of sodium, and the different transporter proteins involved in the sodium coupled glucose uptake are well known (23,61,67,97). Although the electrochemical kinetics of the individual transporter proteins responsible for glucose and nutrient uptake are fairly elucidated (19,54,67,82,97), the combined function in which these transporters drive a net inflow of nutrients from the intestinal lumen to the serosal blood has not yet been modeled in detail.We have developed a mathematical model of an enterocyte that incorporates the available kinetic data from studies on individual transporter proteins. The model includes apical SGLT1 (the glucose sodium cotransporter), coupled apical flow of Na ϩ an...

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The small-intestinal Na+,d-glucose cotransporter: An asymmetric gated channel (or pore) responsive to ΔΨ

Cited by 118 publications

References 75 publications

Kinetics of the Reverse Mode of the Na+/Glucose Cotransporter

Kinetics of the Reverse Mode of the Na+/Glucose Cotransporter

Ischemia induces surface membrane dysfunction. Mechanism of altered Na+-dependent glucose transport.

Transepithelial glucose transport and Na⁺/K⁺ homeostasis in enterocytes: an integrative model

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The small-intestinal Na+,d-glucose cotransporter: An asymmetric gated channel (or pore) responsive to ΔΨ

Cited by 118 publications

References 75 publications

Kinetics of the Reverse Mode of the Na+/Glucose Cotransporter

Kinetics of the Reverse Mode of the Na+/Glucose Cotransporter

Ischemia induces surface membrane dysfunction. Mechanism of altered Na+-dependent glucose transport.

Transepithelial glucose transport and Na+/K+ homeostasis in enterocytes: an integrative model

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Transepithelial glucose transport and Na⁺/K⁺ homeostasis in enterocytes: an integrative model