The neurotoxin 1-methyl-4-phenylpyridinium is a substrate for the canalicular organic cation/H+ exchanger
| Autor: | R H, Moseley, L J, Zugger, R W, Van Dyke |
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| Rok vydání: | 1997 |
| Předmět: |
Male
1-Methyl-4-phenylpyridinium Membrane Glycoproteins Bile Canaliculi Neuropeptides Membrane Transport Proteins Biological Transport Hydrogen-Ion Concentration Tetraethylammonium Compounds Antiporters Rats Adenosine Triphosphate Vesicular Biogenic Amine Transport Proteins Vesicular Monoamine Transport Proteins Animals |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 281(1) |
| ISSN: | 0022-3565 |
| Popis: | Hepatic organic cation transport consists, in part, of carrier-mediated sinusoidal uptake stimulated by an inside-negative membrane potential and canalicular excretion driven by electroneutral organic cation/H+ exchange. Intracellular organic cation transport involves sequestration into acidified organelles, also mediated by organic cation/H+ exchange. A sinusoidal organic cation transporter has been cloned; however, canalicular organic cation transport has not been characterized at the molecular level. On the assumption that hepatic organic cation/H+ exchange resembles monoamine transport in synaptic vesicles, we examined, using canalicular rat liver plasma membrane vesicles, the transport of 1-methyl-4-phenylpyridinium (MPP+), a neurotoxin taken up by a synaptic vesicular monoamine transporter that has been cloned. Under voltage-clamped conditions, an outwardly directed H+ gradient stimulated [3H]MPP+ uptake, compared with uptake under pH-equilibrated conditions, consistent with electroneutral MPP+/H+ exchange. Substrates for canalicular organic cation/H+ exchange cis-inhibited pH-dependent MPP+ uptake. Equilibrium exchange of [14C]tetraethylammonium was inhibited by MPP+ in a concentration-dependent manner, consistent with a direct interaction of MPP+ with the organic cation carrier. Carrier-mediated MPP+ uptake exhibited saturability, with kinetic parameters similarto those described for canalicular tetraethylammonium+/H+ exchange. Canalicular [3H]MPP+ uptake was ATP-independent and, thus, distinct from P-glycoprotein-mediated efflux. The finding that MPP+ is a substrate for canalicular organic cation/H+ exchange is applicable to studies, using degenerate oligonucleotides complementary to sequences conserved in neurotransmitter transporters, aimed at cloning this transporter. |
| Databáze: | OpenAIRE |
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