title: Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain.
abstract: SMCT1 is a sodium-coupled (Na(+)-coupled) transporter for l-lactate and short-chain fatty acids. Here, we show that the ketone bodies, beta-d-hydroxybutyrate and acetoacetate, and the branched-chain ketoacid, alpha-ketoisocaproate, are also substrates for the transporter. The transport of these compounds via human SMCT1 is Na(+)-coupled and electrogenic. The Michaelis constant is 1.4 +/- 0.1 mm for beta-d-hydroxybutyrate, 0.21 +/- 0.04 mm for acetoacetate and 0.21 +/- 0.03 mm for alpha-ketoisocaproate. The Na(+) : substrate stoichiometry is 2 : 1. As l-lactate and ketone bodies constitute primary energy substrates for neurons, we investigated the expression pattern of this transporter in the brain. In situ hybridization studies demonstrate widespread expression of SMCT1 mRNA in mouse brain. Immunofluorescence analysis shows that SMCT1 protein is expressed exclusively in neurons. SMCT1 protein co-localizes with MCT2, a neuron-specific Na(+)-independent monocarboxylate transporter. In contrast, there was no overlap of signals for SMCT1 and MCT1, the latter being expressed only in non-neuronal cells. We also demonstrate the neuron-specific expression of SMCT1 in mixed cultures of rat cortical neurons and astrocytes. This represents the first report of an Na(+)-coupled transport system for a major group of energy substrates in neurons. These findings suggest that SMCT1 may play a critical role in the entry of l-lactate and ketone bodies into neurons by a process driven by an electrochemical Na(+) gradient and hence, contribute to the maintenance of the energy status and function of neurons.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia, USA.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Martin
authors.forename: Elangovan
authors.initials: E
authors.lastname: Gopal
authors.forename: Sudha
authors.initials: S
authors.lastname: Ananth
authors.forename: Lina
authors.initials: L
authors.lastname: Zhuang
authors.forename: Shiro
authors.initials: S
authors.lastname: Itagaki
authors.forename: Balakrishna M
authors.initials: BM
authors.lastname: Prasad
authors.forename: Sylvia B
authors.initials: SB
authors.lastname: Smith
authors.forename: Puttur D
authors.initials: PD
authors.lastname: Prasad
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology* / Q000378:metabolism; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D027682:Cation Transport Proteins / Q000502:physiology*; D002460:Cell Line; D004558:Electric Stimulation / Q000379:methods; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D006885:Hydroxybutyrates / Q000493:pharmacokinetics; D007657:Ketone Bodies / Q000378:metabolism*; D007773:Lactates / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D027501:Monocarboxylic Acid Transporters; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000166:cytology; D012964:Sodium / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014981:Xenopus
chemical_list: D002247:Carbon Isotopes; D027682:Cation Transport Proteins; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D006885:Hydroxybutyrates; D007657:Ketone Bodies; D007773:Lactates; D027501:Monocarboxylic Acid Transporters; C476760:SLC5A8 protein, human; D012964:Sodium; D010751:Phosphopyruvate Hydratase