Dataset Information

Rapid Regulation of Human Multidrug and Extrusion Transporters hMATE1 and hMATE2K.

ABSTRACT: Vectorial transport of organic cations (OCs) in renal proximal tubules is mediated by sequential action of human OC transporter 2 (hOCT2) and human multidrug and toxic extrusion protein 1 and 2K (hMATE1 and hMATE2K), expressed in the basolateral (hOCT2) and luminal (hMATE1 and hMATE2K) plasma membranes, respectively. It is well known that hOCT2 activity is subjected to rapid regulation by several signaling pathways, suggesting that renal OC secretion may be acutely adapted to physiological requirements. Therefore, in this work, the acute regulation of hMATEs stably expressed in human embryonic kidney cells was characterized using the fluorescent substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+) as a marker. A specific regulation of ASP+ transport by hMATE1 and hMATE2K measured in uptake and efflux configurations was observed. In the example of hMATE1 efflux reduction by inhibition of casein kinase II, it was also shown that this regulation is able to modify transcellular transport of ASP+ in Madin-Darby canine kidney II cells expressing hOCT2 and hMATE1 on the basolateral and apical membrane domains, respectively. The activity of hMATEs can be rapidly regulated by some intracellular pathways, which sometimes are common to those found for hOCTs. Interference with these pathways may be important to regulate renal secretion of OCs.

SUBMITTER: Kantauskaite M

PROVIDER: S-EPMC7404265 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Rapid Regulation of Human Multidrug and Extrusion Transporters hMATE1 and hMATE2K.

Kantauskaitė Marta M Hucke Anna A Reike Moritz M Ahmed Eltayeb Sara S Xiao Chuyan C Barz Vivien V Ciarimboli Giuliano G

International journal of molecular sciences 20200721 14

Vectorial transport of organic cations (OCs) in renal proximal tubules is mediated by sequential action of human OC transporter 2 (hOCT2) and human multidrug and toxic extrusion protein 1 and 2K (hMATE1 and hMATE2K), expressed in the basolateral (hOCT2) and luminal (hMATE1 and hMATE2K) plasma membranes, respectively. It is well known that hOCT2 activity is subjected to rapid regulation by several signaling pathways, suggesting that renal OC secretion may be acutely adapted to physiological requi ...[more]

PMID: 32708212

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Project description:Background and Aims: Metformin is the most widely-used anti-diabetic drug in the United States. However, medication management fails to achieve therapeutic goals in ~20% of patients. This study attempted to identify genetic polymorphisms associated with metformin treatment failure. We studied the associations between polymorphisms in two liver and kidney organic cation transporter genes (OCT1 & OCT2) and two kidney multidrug and toxin extrusion transporter genes, (MATE1 & MATE2K) and response to metformin monotherapy. Methods: At Kaiser Permanente Southeast and Marshfield Clinic Research Foundation we identified 304 type 2 diabetes (T2DM) patients on metformin monotherapy who: were enrolled for >=6 months prior to initiation; remained on metformin >= 90 days following initiation; and had a HgbA1c measured prior to first metformin prescription and then after initiation. From this group we selected 171 patients who had not received metformin or other anti-diabetics previously, and had baseline HbA1c levels >7.0% prior to metformin initiation. We genotyped 10 SNPs, and assessed response by measuring absolute and relative change in HbA1c after after metformin initiation. Results: Three SNPs were identified that were significantly associated with reduced response to metformin, after adjustment for baseline HbA1c, dose, and ethnicity. In a dominant model, heterozygosity or homozygosity for minor A allele in the MATE1 intronic SNP, rs2289669, resulted in a smaller absolute change in HbA1c (mean of 0.45% less reduction in absolute change in HbA1c; 95% CI 0.17 to 0.74%) compared to individuals homozygous for major G allele. In a recessive model, homozygosity for minor A allele in MATE2K 5′-UTR SNP, rs12943590, resulted in smaller absolute change in HbA1c (mean of 0.43% less reduction in absolute change in HbA1c, 95% CI 0.053 to 0.86%). The reduced function SNPs in OCT1 & OCT2 were not associated with metformin response, except for rs34059508 (G465R). This SNP showed a positive (but not statistically significant) association with smaller absolute change in HbA1c (mean of 0.49%; 95% CI −0.06354 to 1.045%). Conclusions: These three variants of metformin transporter genes may be important for personalizing treatment for patients with T2DM. A replication study in a larger population is currently being planned.

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Dataset Information

Rapid Regulation of Human Multidrug and Extrusion Transporters hMATE1 and hMATE2K.

Publications

Rapid Regulation of Human Multidrug and Extrusion Transporters hMATE1 and hMATE2K.

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