Kinetics of the Reverse Mode of the Na+/Glucose Cotransporter
Jonna
Terkildsen
Auckland Bioengineering Institute, University of Auckland
Model Status
This CellML model is in the process of being curated, the units are consistent and the model runs in COR and PCEnv. This model does not yet recreate all the published results.
Model Structure
Abstract: 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 a-methyl-D-glucopyranoside (aMDG) 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 current-voltage relationship saturated at positive membrane voltages (30-50 mV), and approached zero at -150 mV. The half-maximal concentration for aMDG-evoked outward current (K_0.5_aMDG) was 35 mM (at 0 mV). In comparison, K_0.5_aMDG for forward sugar transport was 0.15 mM (at 0 mV). K_0.5_Na was similar for forward and reverse transport (~ 35mM at 0 mV). Specificity of SGLT1 for reverse transport was: aMDG (1.0) > D-galactose (0.84) > 3-O-methyl-glucose (0.55) > D-glucose (0.38), whereas for forward transport, specificity was: aMDG ~ D-glucose ~ D-galactose > 3-O-methylglucose. 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.
The original paper reference is cited below:
Kinetics of the Reverse Mode of the Na+/Glucose Cotransporter, S.Eskandari, E.M. Wright and D.D.F. Loo, 2005,
Journal of Membrane Biology
, 204, 23-32.
PubMed ID: 16007500
model diagram
Schematic diagram of the Eskandari et al 2005 SGLT1 model. C' represents the external-facing carrier. C'' represents the internal-facing carrier.
$\mathrm{k0\_65}=\begin{cases}\mathrm{k0\_65\_r} & \text{if $\mathrm{Na\_o}< 100E-3$}\\ \mathrm{k0\_65\_f} & \text{otherwise}\end{cases}\mathrm{k0\_61}=\begin{cases}\mathrm{k0\_61\_r} & \text{if $\mathrm{Na\_o}< 100E-3$}\\ \mathrm{k0\_61\_f} & \text{otherwise}\end{cases}\mathrm{k0\_16}=\begin{cases}\mathrm{k0\_16\_r} & \text{if $\mathrm{Na\_o}< 100E-3$}\\ \mathrm{k0\_16\_f} & \text{otherwise}\end{cases}\mathrm{alpha\_p}=1-\mathrm{delta}-\mathrm{alpha\_pp}\mathrm{C\_T}=\frac{1E6\mathrm{N\_C}}{\mathrm{N\_Avo}}\mathrm{mu}=\frac{FV}{RT}$
$\frac{d V}{d \mathrm{time}}=200E-3$
$\mathrm{ks\_12}=\mathrm{k0\_12}e^{\frac{-n\mathrm{alpha\_p}\mathrm{mu}}{2}}\mathrm{k\_12}=\mathrm{ks\_12}\mathrm{Na\_o}^{n}\mathrm{k\_21}=\mathrm{k0\_21}e^{\frac{n\mathrm{z\_Na}\mathrm{alpha\_p}\mathrm{mu}}{2}}\mathrm{k\_23}=\mathrm{k0\_23}\mathrm{glucose\_o}\mathrm{k\_32}=\mathrm{k0\_32}\mathrm{k\_34}=\mathrm{k0\_34}e^{\frac{-(\mathrm{z\_c}+n)\mathrm{delta}\mathrm{mu}}{2}}\mathrm{k\_43}=\mathrm{k0\_43}e^{\frac{(\mathrm{z\_c}+n)\mathrm{delta}\mathrm{mu}}{2}}\mathrm{k\_45}=\mathrm{k0\_45}\mathrm{k\_54}=\mathrm{k0\_54\_temp}\mathrm{glucose\_i}\mathrm{k\_25}=\mathrm{k0\_25}e^{\frac{-(\mathrm{z\_c}+n)\mathrm{delta}\mathrm{mu}}{2}}\mathrm{k\_52\_temp}=\mathrm{k0\_52}e^{\frac{(\mathrm{z\_c}+n)\mathrm{delta}\mathrm{mu}}{2}}\mathrm{k\_56}=\mathrm{k0\_56}e^{\frac{-n\mathrm{z\_Na}\mathrm{alpha\_pp}\mathrm{mu}}{2}}\mathrm{k\_65}=\mathrm{k0\_65}\mathrm{Na\_i}^{n}e^{\frac{n\mathrm{z\_Na}\mathrm{alpha\_pp}\mathrm{mu}}{2}}\mathrm{k\_61}=\mathrm{k0\_61}e^{\frac{\mathrm{z\_c}\mathrm{delta}\mathrm{mu}}{2}}\mathrm{k\_16}=\mathrm{k0\_16}e^{\frac{-\mathrm{z\_c}\mathrm{delta}\mathrm{mu}}{2}}\mathrm{k\_52}=\frac{\mathrm{k0\_12}\mathrm{k\_25}\mathrm{k0\_56}\mathrm{k0\_61}}{\mathrm{k0\_21}\mathrm{k0\_16}\mathrm{k0\_65}}\mathrm{k0\_54\_temp}=\frac{\mathrm{k0\_23}\mathrm{k\_34}\mathrm{k\_45}\mathrm{k\_52}}{\mathrm{k\_43}\mathrm{k\_32}\mathrm{k\_25}}$
$\frac{d \mathrm{C\_1}}{d \mathrm{time}}=\mathrm{k\_21}\mathrm{C\_2}+\mathrm{k\_61}\mathrm{C\_6}-(\mathrm{k\_12}+\mathrm{k\_16})\mathrm{C\_1}\frac{d \mathrm{C\_2}}{d \mathrm{time}}=\mathrm{k\_12}\mathrm{C\_1}+\mathrm{k\_32}\mathrm{C\_3}+\mathrm{k\_52}\mathrm{C\_5}-(\mathrm{k\_21}+\mathrm{k\_23}+\mathrm{k\_25})\mathrm{C\_2}\frac{d \mathrm{C\_3}}{d \mathrm{time}}=\mathrm{k\_23}\mathrm{C\_2}+\mathrm{k\_43}\mathrm{C\_4}-(\mathrm{k\_32}+\mathrm{k\_34})\mathrm{C\_3}\frac{d \mathrm{C\_4}}{d \mathrm{time}}=\mathrm{k\_34}\mathrm{C\_3}+\mathrm{k\_54}\mathrm{C\_5}-(\mathrm{k\_45}+\mathrm{k\_43})\mathrm{C\_4}\frac{d \mathrm{C\_5}}{d \mathrm{time}}=\mathrm{k\_45}\mathrm{C\_4}+\mathrm{k\_65}\mathrm{C\_6}+\mathrm{k\_25}\mathrm{C\_2}-(\mathrm{k\_54}+\mathrm{k\_52}+\mathrm{k\_56})\mathrm{C\_5}\frac{d \mathrm{C\_6\_temp}}{d \mathrm{time}}=\mathrm{k\_16}\mathrm{C\_1}+\mathrm{k\_56}\mathrm{C\_5}-(\mathrm{k\_61}+\mathrm{k\_65})\mathrm{C\_6\_temp}\mathrm{C\_6}=\mathrm{C\_T}-\mathrm{C\_1}+\mathrm{C\_2}+\mathrm{C\_3}+\mathrm{C\_4}+\mathrm{C\_5}$
$\mathrm{I\_NaGl\_pSS}=-F(n\mathrm{z\_Na}\mathrm{alpha\_p}(\mathrm{k\_12}\mathrm{C\_1}-\mathrm{k\_21}\mathrm{C\_2})+\mathrm{z\_c}\mathrm{delta}(\mathrm{k\_16}\mathrm{C\_1}-\mathrm{k\_61}\mathrm{C\_6})+n\mathrm{z\_Na}\mathrm{alpha\_pp}(\mathrm{k\_56}\mathrm{C\_5}-\mathrm{k\_65}\mathrm{C\_6}))\mathrm{I\_NaGl\_SS}=-F(\mathrm{z\_c}(\mathrm{k\_16}\mathrm{C1}-\mathrm{k\_61}\mathrm{C6})+(\mathrm{z\_c}+\mathrm{z\_Na}n)(\mathrm{k\_25}\mathrm{C2}-\mathrm{k\_52}\mathrm{C5})+(\mathrm{z\_c}+\mathrm{z\_Na}n)(\mathrm{k\_34}\mathrm{C3}-\mathrm{k\_43}\mathrm{C4}))$
Concentration of C6 of the 6-state SGLT1 cotransporter
Concentration of C6 in the luminal compartment
membrane potential measured from luminal to cytosol compartment across apical plasma membrane
Transition rate from state 3 to 4
k_34 is the rate of transition from state 3 to 4 from luminal to cytosol compartment
Transition rate from state 2 to 3
k_23 is the rate of transition from state 2 to 3 in the luminal compartment
k_34 is the rate of transition from state 3 to 4 from luminal to cytosol compartment
fraction of elctrical field sensed by the Na+ binding in the cytosol compartment
Concentration of C2 of the 6-state SGLT1 cotransporter
Concentration of C2 in the cytosol compartment (Parent paper)
fraction of elctrical field sensed by the empty ion binding site from luminal to cytosol compartment and cytosol to luminal compartment
Transition rate from state 4 to 3
k_43 is the rate of transition from state 4 to 3 from cytosol to luminal compartment
Concentration of C5 of the 6-state SGLT1 cotransporter
Concentration of C5 in the luminal compartment
fraction of elctrical field sensed by the Na+ binding in the luminal compartment
Transition rate from state 4 to 5
k_45 is the arte of transition from state 4 to 5 in the cytosol compartment
Transition rate from state 2 to 1
k_21 is the rate of transition from state 2 to 1 in the luminal compartment
Transition rate from state 1 to 2
k_12 is the rate of transition from state 1 to 2 in the luminal compartment
k_23 is the rate of transition from state 2 to 3 in the luminal compartment
Transition rate from state 6 to 1
k_61 is the rate of transition from state 6 to 1 from cytosol to luminal compartment
Transition rate from state 5 to 4
k_54 is the rate of transition from state 5 to 4 in the cytosol compartment
Concentration of glucose in the cytosol compartment
Concentration of C1 of the 6-state SGLT1 cotransporter
Concentration of C1 in the cytosol compartment (Parent paper)
valence of Na+ in the luminal compartment and cytosol compartment
valence of ion binding site on the empty carrier from luminal to cytosol compartment and cytosol to luminal compartment
Concentration of Na+ in the luminal compartment
Transition rate from state 5 to 6
k_56 is the rate of transition from state 5 to 6 in the cytosol compartment
Transition rate from state 2 to 5
k_25 is the rate of transition from state 2 to 5 from luminal to cytosol compartment
Transition rate from state 3 to 2
k_32 is the rate of transition from state 3 to 2 in the luminal compartment
k_56 is the rate of transition from state 5 to 6 in the cytosol compartment
k_32 is the rate of transition from state 3 to 2 in the luminal compartment
k_21 is the rate of transition from state 2 to 1 in the luminal compartment
fraction of elctrical field sensed by the Na+ binding in the cytosol compartment
k_45 is the arte of transition from state 4 to 5 in the cytosol compartment
Total concentration of the 6-state SGLT1 cotransporter
Concentration of 6-state carrier in the luminal and cytosol compartmets of SGLT1
k_43 is the rate of transition from state 4 to 3 from cytosol to luminal compartment
k_45 is the arte of transition from state 4 to 5 in the cytosol compartment
k_21 is the rate of transition from state 2 to 1 in the luminal compartment
k_32 is the rate of transition from state 3 to 2 in the luminal compartment
k_56 is the rate of transition from state 5 to 6 in the cytosol compartment
luminal concentration of Na+ at which the half-maximal current from cytosol to luminal compartment is evoked
Concentration of C5 in the luminal compartment (Parent paper)
Transition rate from state 5 to 2
k_52 is the rate of transition from state 5 to 2 from cytosol to luminal compartment
fraction of elctrical field sensed by the Na+ binding in the cytosol compartment
k_54 is the rate of transition from state 5 to 4 in the cytosol compartment
k_54 is the rate of transition from state 5 to 4 in the cytosol compartment
Concentration of C2 in the cytosol compartment
k_23 is the rate of transition from state 2 to 3 in the luminal compartment
Concentration of C4 of the 6-state SGLT1 cotransporter
Concentration of C4 in the luminal compartment (Parent paper)
Transition rate from state 6 to 5
k_65 is the rate of transition from state 6 to 5 in the cytosol compartment
k_65 is the rate of transition from state 6 to 5 in the cytosol compartment
Na+ flow through apical plasma membrane
presteady state current is given by sum of all translocation steps involving the transfer of a net charge in the cell membrane of SGLT1
Concentration of Na+ in the cytosol compartment
k_43 is the rate of transition from state 4 to 3 from cytosol to luminal compartment
Transition rate from state 1 to 6
k_16 is the rate of transition from state 1 to 6 from luminal to cytosol compartment
k_34 is the rate of transition from state 3 to 4 from luminal to cytosol compartment
Concentration of C1 in the cytosol compartment
Concentration of glucose in the luminal compartment
Concentration of glucose in the luminal compartment
k_52 is the rate of transition from state 5 to 2 from cytosol to luminal compartment
k_25 is the rate of transition from state 2 to 5 from luminal to cytosol compartment
Concentration of C4 in the luminal compartment
k_52 is the rate of transition from state 5 to 2 from cytosol to luminal compartment
Concentration of C6 in the luminal compartment (Parent paper)
k_61 is the rate of transition from state 6 to 1 from cytosol to luminal compartment
k_43 is the rate of transition from state 4 to 3 from cytosol to luminal compartment
Concentration of glucose in the luminal compartment
k_65 is the rate of transition from state 6 to 5 in the cytosol compartment
Concentration of C3 of the 6-state SGLT1 cotransporter
Concentration of C3 in the cytosol compartment
k_12 is the rate of transition from state 1 to 2 in the luminal compartment
Concentration of Na+ in the cytosol compartment
Concentration of C1 in the cytosol compartment (Parent paper)
Concentration of C5 in the luminal compartment
k_56 is the rate of transition from state 5 to 6 in the cytosol compartment
Concentration of Na+ in the luminal compartment
Concentration of 6-state carrier in the luminal and cytosol compartmets of SGLT1
fraction of elctrical field sensed by the empty ion binding site from luminal to cytosol compartment and cytosol to luminal compartment
k_21 is the rate of transition from state 2 to 1 in the luminal compartment
Concentration of C6 in the luminal compartment
k_61 is the rate of transition from state 6 to 1 from cytosol to luminal compartment
k_52 is the rate of transition from state 5 to 2 from cytosol to luminal compartment
Concentration of 6-state carrier in the luminal and cytosol compartmets of SGLT1
k_16 is the rate of transition from state 1 to 6 from luminal to cytosol compartment
fraction of elctrical field sensed by the Na+ binding in the luminal compartment
Concentration of C3 in the cytosol compartment (Parent paper)
k_65 is the rate of transition from state 6 to 5 in the cytosol compartment
k_34 is the rate of transition from state 3 to 4 from luminal to cytosol compartment
electrochemical potential which is measured in the cell membrane from luminal to cytosol compartment and cytosol to luminal compartment
k_16 is the rate of transition from state 1 to 6 from luminal to cytosol compartment
k_61 is the rate of transition from state 6 to 1 from cytosol to luminal compartment
Concentration of Na+ in the luminal compartment
Concentration of 6-state carrier in the luminal and cytosol compartments of SGLT1
Concentration of C3 in the cytosol compartment
membrane potential measured from luminal to cytosol compartment across apical plasma membrane
Concentration of C2 in the cytosol compartment (Parent paper)
Concentration of Na+ in the luminal compartment
k_54 is the rate of transition from state 5 to 4 in the cytosol compartment
k_16 is the rate of transition from state 1 to 6 from luminal to cytosol compartment
valence of ion binding site on the empty carrier from luminal to cytosol compartment and cytosol to luminal compartment
Concentration of C4 in the luminal compartment
D.D.F. Loo
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 a-methyl-D-glucopyranoside (aMDG) 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 current-voltage relationship saturated at positive membrane voltages (30-50 mV), and approached zero at -150 mV. The half-maximal concentration for aMDG-evoked outward current (K_0.5_aMDG) was 35 mM (at 0 mV). In comparison, K_0.5_aMDG for forward sugar transport was 0.15 mM (at 0 mV). K_0.5_Na was similar for forward and reverse transport (~ 35mM at 0 mV). Specificity of SGLT1 for reverse transport was: aMDG (1.0) > D-galactose (0.84) > 3-O-methyl-glucose (0.55) > D-glucose (0.38), whereas for forward transport, specificity was: aMDG ~ D-glucose ~ D-galactose > 3-O-methylglucose. 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.
Xenopus oocyte
Reverse sugar transport
S. Eskandari
E.M. Wright
Kinetics of the Reverse Mode of the Na+/Glucose Cotransporter
k_61 is the rate of transition from state 6 to 1 from cytosol to luminal compartment
fraction of elctrical field sensed by the Na+ binding in the luminal compartment
Concentration of C6 in the luminal compartment (Parent paper)
k_43 is the rate of transition from state 4 to 3 from cytosol to luminal compartment
k_12 is the rate of transition from state 1 to 2 in the luminal compartment
Concentration of C1 in the cytosol compartment
valence of Na+ in the luminal compartment and cytosol compartment
luminal concentration of sugar at which the half-maximal current from cytosol to luminal compartment is evoked
electrochemical potential which is measured in the cell membrane from luminal to cytosol compartment and cytosol to luminal compartment
k_32 is the rate of transition from state 3 to 2 in the luminal compartment
Concentration of C5 in the luminal compartment (Parent paper)
k_25 is the rate of transition from state 2 to 5 from luminal to cytosol compartment
valence of Na+ in the luminal compartment and cytosol compartment
k_56 is the rate of transition from state 5 to 6 in the cytosol compartment
Concentration of glucose in the cytosol compartment
k_25 is the rate of transition from state 2 to 5 from luminal to cytosol compartment
valence of ion binding site on the empty carrier from luminal to cytosol compartment and cytosol to luminal compartment
Concentration of C2 in the cytosol compartment
k_21 is the rate of transition from state 2 to 1 in the luminal compartment
Concentration of C4 in the luminal compartment (Parent paper)
k_12 is the rate of transition from state 1 to 2 in the luminal compartment
k_45 is the arte of transition from state 4 to 5 in the cytosol compartment
k_12 is the rate of transition from state 1 to 2 in the luminal compartment
k_65 is the rate of transition from state 6 to 5 in the cytosol compartment
fraction of elctrical field sensed by the empty ion binding site from luminal to cytosol compartment and cytosol to luminal compartment
k_25 is the rate of transition from state 2 to 5 from luminal to cytosol compartment
Concentration of 6-state carrier in the luminal and cytosol compartmets of SGLT1
k_16 is the rate of transition from state 1 to 6 from luminal to cytosol compartment
k_23 is the rate of transition from state 2 to 3 in the luminal compartment
k_34 is the rate of transition from state 3 to 4 from luminal to cytosol compartment
k_52 is the rate of transition from state 5 to 2 from cytosol to luminal compartment
Concentration of C3 in the cytosol compartment (Parent paper)