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J. Biol. Chem., Vol. 282, Issue 16, 11996-12009, April 20, 2007

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Zebrafish Slc5a12 Encodes an Electroneutral Sodium Monocarboxylate Transporter (SMCTn)

A COMPARISON WITH THE ELECTROGENIC SMCT (SMCTe/Slc5a8)^*

Consuelo Plata¹, Caroline R. Sussman^¶, Aleksandra Sini^¶1, Jennifer O. Liang^||, David B. Mount^**2, Zara M. Josephs, Min-Hwang Chang, and Michael F. Romero^¶3

From the Departments of Physiology and Biophysics and ^||Biology, Case Western Reserve University, Cleveland, Ohio 44106, Departamento de Nefrología y Metabolismo Mineral, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan 14000, México City, México, ^¶Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, and ^**Renal Division, Brigham and Women's Hospital and Division of General Internal Medicine, Veterans Affairs Boston Healthcare System, Harvard Medical School, Boston, Massachusetts 02115

We have identified and characterized two different sodium-coupled monocarboxylate cotransporters (SMCT) from zebrafish (Danio rerio), electrogenic (zSMCTe) and electroneutral (zSMCTn). zSMCTn is the 12th member of the zebrafish Slc5 gene family (zSlc5a12). Both zSMCT sequences have 50% homology to human SLC5A8 (hSMCT). Transport function and kinetics were measured in Xenopus oocytes injected with zSMCT cRNAs by measurement of intracellular Na⁺ concentration ([Na⁺]_i) and membrane potential. Both zSMCTs oocytes increased [Na⁺]_i with addition of monocarboxylates (MC) such as lactate, pyruvate, nicotinate, and butyrate. By using two electrode voltage clamp experiments, we measured currents elicited from zSMCTe after MC addition. MC-elicited currents from zSMCTe were similar to hSMCT currents. In contrast, we found no significant MC-elicited current in either zSMCTn or control oocytes. Kinetic data show that zSMCTe has a higher affinity for lactate, nicotinate, and pyruvate (K_m^L-lactate = 0.17 ± 0.02 mM, K_m^nicotinate = 0.54 ± 0.12 mM at -150 mV) than zSMCTn (K_m^L-lactate = 1.81 ± 0.19 mM, K_m^nicotinate = 23.68 ± 4.88 mM). In situ hybridization showed that 1-, 3-, and 5-day-old zebrafish embryos abundantly express both zSMCTs in the brain, eyes, intestine, and kidney. Within the kidney, zSMCTn mRNA is expressed in pronephric tubules, whereas zSMCTe mRNA is more distal in pronephric ducts. zSMCTn is expressed in exocrine pancreas, but zSMCTe is not. Roles for Na⁺-coupled monocarboxylate cotransporters have not been described for the brain or eye. In summary, zSMCTe is the zebrafish SLC5A8 ortholog, and zSMCTn is a novel, electroneutral SMCT (zSlc5a12). Slc5a12 in higher vertebrates is likely responsible for the electroneutral Na⁺/lactate cotransport reported in mammalian and amphibian kidneys.

Received for publication, October 2, 2006 , and in revised form, January 18, 2007.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY727859 [GenBank] and AY727860 [GenBank] .

^* This work was supported in part by National Institutes of Health Grants DK-56218 (to M. F. R.), DK-60845 (to M. F. R.), and DK-57708 (to D. B. M.), a grant from the Wadsworth Foundation (to C. R. S.), from the American Heart Association Grant SDG06-301037N (to C.R.S.), from the Mexican Council of Science and Technology Grant 48709M (to C.P.), and a postdoctoral fellowship from the American Heart Association Ohio Valley Affiliate (to M.-H. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by National Institutes of Health Grant DK59985 (to R. T. Miller).

² Supported by Veterans Affairs.

³ To whom correspondence should be addressed: Dept. of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, 200 First St. SW, Guggenheim 9-21D, Rochester, MN 55905. Tel.: 507-284-8127; Fax: 484-450-0475; E-mail: romero.michael{at}mayo.edu.

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