Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle.

Article Details

Citation

Manning Fox JE, Meredith D, Halestrap AP

Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle.

J Physiol. 2000 Dec 1;529 Pt 2:285-93.

PubMed ID
11101640 [ View in PubMed
]
Abstract

Monocarboxylate transporter (MCT) 4 is the major monocarboxylate transporter isoform present in white skeletal muscle and is responsible for the efflux of lactic acid produced by glycolysis. Here we report the characterisation of MCT4 expressed in Xenopus oocytes. The protein was correctly targeted to the plasma membrane and rates of substrate transport were determined from the rate of intracellular acidification monitored with the pH-sensitive dye 2', 7'-bis-(carboxyethyl)-5(6)-carboxyfluorescein (BCECF). In order to validate the technique, the kinetics of monocarboxylate transport were measured in oocytes expressing MCT1. Km values determined for L-lactate, D-lactate and pyruvate of 4.4, > 60 and 2.1 mM, respectively, were similar to those determined previously in tumour cells. Comparison of the time course of [14C]lactate accumulation with the rate of intracellular acidification monitored with BCECF suggests that the latter reflects pH changes close to the plasma membrane associated with transport, whilst the former may include diffusion-limited movement of lactate into the bulk cytosol. Km values of MCT4 for these substrates were found to be 28, 519 and 153 mM, respectively, and for a range of other monocarboxylates values were at least an order of magnitude higher than for MCT1. Vmax values appeared to be similar for all substrates. K0.5 values of MCT4 (determined at 30 mM L-lactate) for inhibition by alpha-cyano-4-hydroxycinnamate (991 microM), phloretin (41 microM), 5-nitro-2-(3-phenylpropylamino)benzoate (240 microM), p-chloromercuribenzene sulphonate (21 microM) and 3-isobutyl-1-methylxanthine (970 microM, partial inhibition) were also substantially higher than for MCT1. No inhibition of MCT4 by 2 mM 4,4'-diisothiocyanostilbene-2,2'-disulphonate was observed. The properties of MCT4 are consistent with published data on giant sarcolemmal vesicles in which MCT4 is the dominant MCT isoform, and are appropriate for the proposed role of MCT4 in mediating the efflux from the cell of glycolytically derived lactic acid but not pyruvate.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
Acetoacetic acidMonocarboxylate transporter 4ProteinHumans
Unknown
Substrate
Details
alpha-KetoisovalerateMonocarboxylate transporter 4ProteinHumans
Unknown
Substrate
Details
D-Lactic acidMonocarboxylate transporter 4ProteinHumans
Unknown
Substrate
Details
Formic acidMonocarboxylate transporter 4ProteinHumans
Unknown
Substrate
Details
gamma-Hydroxybutyric acidMonocarboxylate transporter 4ProteinHumans
Unknown
Substrate
Details
Glyoxylic acidMonocarboxylate transporter 4ProteinHumans
Unknown
Substrate
Details
Lactic acidMonocarboxylate transporter 4ProteinHumans
Unknown
Substrate
Details
Oxamic AcidMonocarboxylate transporter 4ProteinHumans
Unknown
Substrate
Details
Phenylpyruvic acidMonocarboxylate transporter 4ProteinHumans
Unknown
Substrate
Details
Pyruvic acidMonocarboxylate transporter 4ProteinHumans
Unknown
Substrate
Details