Interaction of Organic Cations with a Newly Identified Plasma Membrane Monoamine Transporter

Abstract

Many endogenous compounds and xenobiotics are organic cations that rely on polyspecific organic cation transporters (OCTs) to traverse cell membranes. We recently cloned a novel human plasma membrane monoamine transporter (PMAT) that belongs to the equilibrative nucleoside transporter (ENT) family. We have reported previously that, unlike other ENTs, PMAT (also known as ENT4) is a Na ϩ -independent and membrane potential-sensitive transporter that transports monoamine neurotransmitters and the neurotoxin 1-methyl-4-phenylpyridinium (MPP ϩ ). These compounds are the known substrates for OCTs, which raises the possibility that PMAT functions as a polyspecific transporter like the OCTs. In the present study, we analyzed the interaction of PMAT with a series of structurally diverse organic cations using MDCK cells stably expressing human PMAT. Our study showed that PMAT interacts with many organic cations that have heterogeneous chemical structures. PMAT transports classic OCT substrates, such as tetraethylammonium, guanidine, and histamine. Prototype OCT inhibitors, including cimetidine, and type II cations (e.g., quinidine, quinine, verapamil, and rhodamine123) are also PMAT inhibitors. An analysis of molecular structures and apparent binding affinities revealed that charge and hydrophobicity are the principal determinants for transporter-substrate/ inhibitor interaction. A planar aromatic mass seems to be important for high affinity interaction. trans-Stimulation and efflux studies demonstrate that PMAT is able to mediate bidirectional transport. These functional properties of PMAT are strikingly similar to those of the OCTs. We therefore conclude that PMAT can function as a polyspecific organic cation transporter, which may play a role in organic cation transport in vivo.

Clonidine Transport at the Mouse Blood—Brain Barrier by a New H+ Antiporter that Interacts with Addictive Drugs

“…Other chemical inhibitions rule out the involvement of the choline transporters, PMAT, and carnitine transporters, OCTN2-3 (Inazu et al, 2005;Wu et al, 1999). Moreover, PMAT is sensitive to the trans-membrane potential and is inhibited by dopamine, histamine, and cimetidine (Engel et al, 2004;Engel and Wang, 2005;Xia et al, 2007). Thus, these experiments suggest that clonidine transport at the mouse luminal BBB is mediated by a new organic cation/H + antiporter, as suggested in other cells (Fischer et al, 2006(Fischer et al, , 2007.…”

Evidence for significant contribution of a newly identified monoamine transporter (PMAT) to serotonin uptake in the human brain

“…It has also been demonstrated that in hypothalamus, corpus callosum and optic nerves of rat brain, 5-HT uptake under Na + -free condition accounted for about 20% of total uptake, and fluoxetine, a potent inhibitor of SERT, only caused a 57% decrease in 5-HT uptake [28]. Most recently, a study reported that local perfusion of decynium 22, a high affinity inhibitor of OCT and PMAT (K i = 0.1 μM) [29], resulted in a significant, dose-dependent increase in extracellular 5-HT level in rat dorsomedial hypothalamus where SERT is minimally expressed [25]. Therefore, PMAT, together with the OCTs, may play a significant role in 5-HT clearance in brain regions where expression of SERT is low or when SERT function is pharmacologically inhibited, such as chronic use of antidepressants.…”

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

“…The plasma membrane monoamine transporter (PMAT; SLC29A4), identified in 2004, accepts structurally diverse hydrophilic organic cations as substrates, such as 1-methyl-4-phenylpyridinium (MPP + ), tetraethylammonium, serotonin, dopamine, epinephrine, norepinephrine, guanidine, and histamine 34,35 . In immunofluorescence studies 36 ,Xia et al showed that PMAT is primarily targeted to the apical membrane of polarized epithelial cells .…”