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1 Groupe d'étude des protéines membranaires, Pavillon Paul-G-Desmarais, 2960 chemin de la Tour, Université de Montréal, Montreal, QC, Canada, H3T 1J42 Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA3 Ireland Cancer Center and Department of Medicine, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH 44106, USA4 Howard Hughes Medical Institute
The orphan cotransport protein expressed by the SLC5A8 gene has been shown to play a role in controlling the growth of colon cancers, and the silencing of this gene is a common and early event in human colon neoplasia. We expressed this protein in Xenopus laevis oocytes and have found that it transports small monocarboxylic acids. The electrogenic activity of the cotransporter, which we have named SMCT (sodium monocarboxylate transporter), was dependent on external Na+ and was compatible with a 3 : 1 stoichiometry between Na+ and monocarboxylates. A portion of the SMCT-mediated current was also Cl– dependent, but Cl– was not cotransported. SMCT transports a variety of monocarboxylates (similar to unrelated monocarboxylate transport proteins) and most transported monocarboxylates demonstrated Km values near 100 µM, apart from acetate and D-lactate, for which the protein showed less affinity. SMCT was strongly inhibited by 1 mM probenecid or ibuprofen. In the absence of external substrate, a Na+-independent leak current was also observed to pass through SMCT. SMCT activity was strongly inhibited after prolonged exposure to high external concentrations of monocarboxylates. The transport of monocarboxylates in anionic form was confirmed by the observation of a concomitant alkalinization of the cytosol. SMCT, being expressed in colon and kidney, represents a novel means by which Na+, short-chain fatty acids and other monocarboxylates are transported in these tissues. The significance of a Na+–monocarboxylate transporter to colon cancer presumably stems from the transport of butyrate, which is well known for having anti-proliferative and apoptosis-inducing activity in colon epithelial cells.
(Received 3 March 2004;
accepted after revision 16 April 2004;
first published online 16 April 2004)
Corresponding author J.-Y. Lapointe: Physics Department, Université de Montréal, PO Box 6128, succ. ‘centre-ville’, Montreal, QC, Canada, H3C 3J7. Email: jean-yves.lapointe{at}umontreal.ca
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