Arginine‐427 in the Na<sup>+</sup>/glucose cotransporter (SGLT1) is involved in trafficking to the plasma membrane

Lostao, M. P.; Hirayama, Bruce A.; Panayotova‐Heiermann, Mariana; Sampogna, Sharon; Bok, Dean; Wright, Ernest M.

doi:10.1016/0014-5793(95)01339-3

Cited by 32 publications

(33 citation statements)

References 11 publications

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“…Because the inhibition occurs via decrease in V max and is observed within hours, this type of regulation might theoretically be achieved by a decrease in the number of active molecules at the membrane due to endocytic retrieval from and/or exocytic insertion into the plasma membrane and/or rapid degradation by changes in the turnover number of individual exchanger molecules. Multiple plasma membrane transport proteins (7,16,29,37,48) were also shown to be regulated, at least in part, by cellular redistribution (endocytic retrieval from and/or exocytic insertion into the plasma membrane). PKC was reported to generally stimulate apical but not basolateral endocytosis in Caco-2 cells (18).…”

Section: /Ohmentioning

confidence: 99%

Inhibition of apical Cl⁻/OH⁻ exchange activity in Caco-2 cells by phorbol esters is mediated by PKCε

Saksena

Gill

Syed

et al. 2002

American Journal of Physiology-Cell Physiology

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The present studies were undertaken to examine the possible regulation of apical membrane Cl−/OH− exchanger in Caco-2 cells by protein kinase C (PKC). The effect of the phorbol ester phorbol 12-myristate 13-acetate (PMA), an in vitro PKC agonist, on OH−gradient-driven 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS)-sensitive 36Cl uptake in Caco-2 cells was assessed. The results demonstrated that PMA decreased apical Cl−/OH− exchanger activity via phosphatidylinositol 3-kinase (PI3-kinase)-mediated activation of PKCε. The data consistent with these conclusions are as follows: 1) short-term treatment of cells for 1–2 h with PMA (100 nM) significantly decreased Cl−/OH−exchange activity compared with control (4α-PMA); 2) pretreatment of cells with specific PKC inhibitors chelerythrine chloride, calphostin C, and GF-109203X completely blocked the inhibition of Cl−/OH− exchange activity by PMA; 3) specific inhibitors for PKCε (Ro-318220) but not PKCα (Go-6976) significantly blocked the PMA-mediated inhibition; 4) specific PI3-kinase inhibitors wortmannin and LY-294002 significantly attenuated the inhibitory effect of PMA; and 5) PI3-kinase activators IRS-1 peptide and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] mimicked the effects of PMA. These findings provide the first evidence for PKCε-mediated inhibition of Cl−/OH− exchange activity in Caco-2 cells and indicate the involvement of the PI3-kinase-mediated pathways in the regulation of Cl− absorption in intestinal epithelial cells.

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Section: /Ohmentioning

confidence: 99%

Inhibition of apical Cl⁻/OH⁻ exchange activity in Caco-2 cells by phorbol esters is mediated by PKCε

Saksena

Gill

Syed

et al. 2002

American Journal of Physiology-Cell Physiology

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“…Often, di-leucine endocytic signals occur close to arginine-based signals (Kalandadze et al, 2004). A previous study indicates that arginine-427 plays a critical role in the trafficking of the sodium-dependent glucose cotransporter (SGLT1) to the plasma membrane (Lostao et al, 1995), suggesting that the charged residue is essential in membrane protein trafficking. The disruption of R206 by the genetic variant cysteine and other substitutions might interfere with the conversed arginine-based motif (-LLFRLL-) (Fig.…”

Section: Oct1 Genetic Variants Metformin Asian Population 49mentioning

confidence: 99%

Genetic Polymorphisms in Organic Cation Transporter 1 (OCT1) in Chinese and Japanese Populations Exhibit Altered Function

Chen

Takizawa

Chen

et al. 2010

J Pharmacol Exp Ther

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Organic cation transporter 1 (OCT1; SLC22A1) seems to play a role in the efficacy and disposition of the widely used antidiabetic drug metformin. Genetic variants in OCT1 have been identified largely in European populations. Metformin is increasingly being used in Asian populations where the incidence of type 2 diabetes (T2D) is on the rise. The goal of this study is to identify genetic variants of OCT1 in Chinese and Japanese populations, which may potentially modulate response to metformin. We used recent data from the 1000 Genomes Project (Chinese and Japanese) and direct sequencing of selected amplicons of OCT1 in 66 DNA samples from Japanese patients with T2D. A total of six nonsynonymous variants were identified. Three of them (Q97K, P117L, and R206C) had not been functionally characterized previously and had allele frequencies of 0.017, 0.023 and 0.008, respectively. The uptake of metformin in cells expressing Q97K, P117L, and R206C was significantly reduced relative to the OCT1 reference (62 Ϯ 4.3, 55 Ϯ 6.8, and 22 Ϯ 1.5% for Q97K, P117L, and R206C, respectively). Kinetic studies indicated that P117L and R206C exhibited a reduced V max , whereas Q97K showed an increased K m . The green fluorescent protein (GFP)-tagged Q97K and P117L variants localized to the plasma membrane, whereas the GFP-tagged R206C was retained mainly in the endoplasmic reticulum. Replacement of the highly conserved R206 with different amino acids modulated the subcellular localization and function of the transporter. This study suggests that nonsynonymous variants of OCT1 in Chinese and Japanese populations may affect the differential response to metformin.

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“…A number of studies have combined site-directed mutagenesis with the oocyte expression system to identify residues that contribute to the functioning of SGLT1 and its proper trafficking to the plasma membrane (6,7). A set of glycosylation mutants has yielded information on topology, and a chimera of the high affinity and low affinity isoforms has suggested that sugar binding is determined by the C-terminal half of the protein (8).…”

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confidence: 99%

Replacement of Ala-166 with Cysteine in the High Affinity Rabbit Sodium/Glucose Transporter Alters Transport Kinetics and Allows Methanethiosulfonate Ethylamine to Inhibit Transporter Function

Lo¹,

Silverman

1998

Journal of Biological Chemistry

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An alanine to cysteine mutation at position 166 has been introduced by site-directed mutagenesis into the rabbit sodium/glucose transporter (rSGLT1). When expressed in Xenopus laevis oocytes, this mutant transporter (A166C rSGLT1) demonstrates a significantly lower apparent affinity for ␣-methyl glucoside (␣MG) compared with the wild-type transporter (apparent K m ‫؍‬ 0.8 versus 0.15 mM). Using the two-electrode voltage clamp technique, transient currents have also been measured, and for the mutant transporter, the transients induced by large depolarizations exhibit longer time constants than those for wild type. Moreover, the substitution of Ala-166 with a cysteine allows the sulfydryl specific reagent, methanethiosulfonate ethylamine (MTSEA), to react with and alter the function of the transporter. Whereas the wild-type transporter is unaffected by reaction with MTSEA, A166C rSGLT1 has its steady-state currents induced by 1 mM ␣MG inhibited 83% within a minute of exposure to MTSEA. Furthermore, the pre-steady-state transients of the A166C mutant after MTSEA exposure demonstrate much shorter time constants than before while the total amount of charge transferred is only slightly diminished. These results together provide evidence that position 166 is situated in a region critical to the functioning of rSGLT1.

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Arginine‐427 in the Na⁺/glucose cotransporter (SGLT1) is involved in trafficking to the plasma membrane

Cited by 32 publications

References 11 publications

Inhibition of apical Cl⁻/OH⁻ exchange activity in Caco-2 cells by phorbol esters is mediated by PKCε

Inhibition of apical Cl⁻/OH⁻ exchange activity in Caco-2 cells by phorbol esters is mediated by PKCε

Genetic Polymorphisms in Organic Cation Transporter 1 (OCT1) in Chinese and Japanese Populations Exhibit Altered Function

Replacement of Ala-166 with Cysteine in the High Affinity Rabbit Sodium/Glucose Transporter Alters Transport Kinetics and Allows Methanethiosulfonate Ethylamine to Inhibit Transporter Function

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Arginine‐427 in the Na+/glucose cotransporter (SGLT1) is involved in trafficking to the plasma membrane

Cited by 32 publications

References 11 publications

Inhibition of apical Cl−/OH− exchange activity in Caco-2 cells by phorbol esters is mediated by PKCε

Inhibition of apical Cl−/OH− exchange activity in Caco-2 cells by phorbol esters is mediated by PKCε

Genetic Polymorphisms in Organic Cation Transporter 1 (OCT1) in Chinese and Japanese Populations Exhibit Altered Function

Replacement of Ala-166 with Cysteine in the High Affinity Rabbit Sodium/Glucose Transporter Alters Transport Kinetics and Allows Methanethiosulfonate Ethylamine to Inhibit Transporter Function

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Arginine‐427 in the Na⁺/glucose cotransporter (SGLT1) is involved in trafficking to the plasma membrane

Inhibition of apical Cl⁻/OH⁻ exchange activity in Caco-2 cells by phorbol esters is mediated by PKCε

Inhibition of apical Cl⁻/OH⁻ exchange activity in Caco-2 cells by phorbol esters is mediated by PKCε