Deletion of v7-3 (SLC6A15) transporter allows assessment of its roles in synaptosomal proline uptake, leucine uptake and behaviors

Brain Res. 2007 Dec 5:1183:10-20. doi: 10.1016/j.brainres.2007.09.001. Epub 2007 Sep 14.

Abstract

V7-3 (SLC6A15) is the prototype for a gene subfamily whose members have sequence homologies to classical Na+- and Cl(-)-dependent neurotransmitter transporters but display unusual features that include characteristic large fourth extracellular loops. Interest in v7-3 has been increased by the elucidation of its expression in neurons located in cerebral cortex, hippocampus, cerebellum, midbrain and olfactory bulb. To help clarify the role of v7-3 in brain functions, we have created and characterized v7-3 knockout mice. These mice lack functional v7-3 protein but are viable and fertile. While our studies were in progress, v7-3 expression was reported to confer transport of proline and branched-chain amino acids in in vitro expression systems [Takanaga, H., Mackenzie, B., Peng, J.B., Hediger, M.A., 2005b. Characterization of a branched-chain amino-acid transporter SBAT1 (SLC6A15) that is expressed in human brain. Biochem. Biophys. Res. Commun. 337, 892-900; Broer, A., Tietze, N., Kowalczuk, S., Chubb, S., Munzinger, M., Bak, L.K., Broer, S., 2006. The orphan transporter v7-3 (slc6a15) is a Na+-dependent neutral amino acid transporter (B0AT2). Biochem. J. 393, 421-430]. Assessment of amino acid uptake into cortical synaptosomes of v7-3 knockouts identified 15% and 40% reductions in sodium-dependent proline and leucine transport, respectively, compared to wild type controls. Despite these biochemical changes, v7-3 knockout mice demonstrate only modest alterations in rotarod performance with aging and lack reproducible alterations in other motor, memory, anxiety or olfactory tests. Compensation for the lack of v7-3 via other amino acid carriers is likely to leave v7-3 knockouts without gross behavioral manifestations. The current results place v7-3 in the context of other brain transporters that accumulate proline and branched-chain amino acids.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Transport Systems, Neutral / physiology*
  • Animals
  • Behavior, Animal / physiology*
  • Biological Transport, Active / drug effects
  • Biological Transport, Active / genetics
  • Biological Transport, Active / physiology
  • Cysteine / pharmacology
  • DNA Primers
  • Gene Deletion
  • Hydrogen-Ion Concentration
  • Leucine / physiology*
  • Maze Learning / drug effects
  • Mice
  • Mice, Knockout
  • Motor Activity / physiology
  • Phenotype
  • Postural Balance / physiology
  • Proline / metabolism*
  • Psychomotor Performance / physiology
  • Smell / drug effects
  • Synaptosomes / metabolism*

Substances

  • Amino Acid Transport Systems, Neutral
  • DNA Primers
  • Slc6a15 protein, mouse
  • Proline
  • Leucine
  • Cysteine