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

Marta Kantauskaitė,Sara Ahmed Eltayeb,Giuliano Ciarimboli,Moritz Reike,Anna Hucke,Chuyan Xiao,Vivien Barz

doi:10.3390/ijms21145157

Marta Kantauskaitė, Sara Ahmed Eltayeb + Show 5 more

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https://doi.org/10.3390/ijms21145157

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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.

Highlights

Kidneys are key players in the excretion of several substances of endogenous and exogenous origin
ResBuolttsh human embryonic kidney (HEK) 293 cell lines transfected with either hMATE1 or hMABTotEh2Khuwmearne eamblberytoontircanksipdonrety 4(-H(4E-dKi)m2e9th3ylcaemll inlionsetsyrtirla)-nNsf-emcteetdhywlpiythrideiinthiuemr h(MASAPT+E)1inora hcMonAcTeEnt2rKatiowne-rdeepaebnldeentot mtraannnsepro. rStpe4c-i(fi4c-duimpteatkheywlaamsicnaolsctuylraitle)-dNb-ymseuthbytrlapcytrioidninoifuumnsp(AecSiPfi+c)uipntakae cocanlcceunlatrteadtioinn-tdheeppernedseennctemoafn1nmerM
Because of the huge regulatory effects of p56lck and CKII inhibition on ASP+ uptake by hMATE2K, we investigated whether this regulation was due to the activity of Na+/H+ exchanger 1 (NHE1), which is the main regulator of pH in HEK cells [28]

Summary

Introduction

Kidneys are key players in the excretion of several substances of endogenous and exogenous origin. Besides by filtration in glomeruli, renal excretory function is sustained by secretion through the proximal tubules [1,2]. Tubular secretion is especially important for polar and charged molecules, which are subjected to a vectorial transport across proximal tubule cells by the orchestrated action of membrane transporters expressed either in the basolateral (facing blood) or apical (facing primary urine) membrane of the cells. Tubular secretion is responsible for renal excretion of charged molecules, such as organic cations (OCs). Endogenous OCs are substances with important physiological function, such as serotonin and histamine, or are metabolism products, such as creatinine. The human organic cation transporter 2 (hOCT2) expressed in the basolateral membrane of proximal tubule cells mediates the first step of OC secretion, that is, the Na+- and H+-independent. In this work, the acute regulation of hMATEs has been comparatively investigated

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