Biochemistry Select

Transporter proteins bind ions and small molecules and transfer them across lipid membranes. Recent studies on transporters, discussed in this issue's Biochemistry Select, provide insight into the family of proteins targeted by tricyclic antidepressants. Other work sheds light on glucose absorption in the gut, host-pathogen interactions , and a mechanism used by an important food crop to adapt to acidic soil conditions. Tricyclic antidepressants inhibit the reuptake of neurotransmitters, such as serotonin, dopamine, and norepinephrine, by blocking the activity of the corresponding neurotrans-mitter transporter. These neurotransmitter transporters are part of a larger family of sodium cotransporters that transport sodium ions using an existing sodium gradient in order to simultaneously drive the uptake of small compounds, such as neurotransmitters or amino acids. Two recent structures by Singh et al. (2007) and Zhou et al. (2007) now reveal how tricyclic antidepressants interact with this family of cotransporters. Both groups studied a bacterial homolog of the mammalian proteins, the leucine transporter LeuT from Aquifex aeolius, and showed that its activity is also sensitive to tricyclic antidepressants. To gain insight into the mechanism for this effect the two groups cocrystallized LeuT bound to tricyclic antidepressants (clomipramine, desipramine, and imipramine in the case of Singh et al.; desipramine in the case of Zhou et al.). The resulting structures reveal that tricyclic antidepressants bind to LeuT in the region just above the extracellular gate, stabilizing it in a closed position, and trapping the substrate (in this case leucine along with two sodium ions), thereby blocking transport. The findings by these two groups may aid in the design of new inhibitors of this important class of neurotransmitter transport proteins. To support the notion that the basic mode of binding for desipramine is likely conserved between its mammalian and bacterial targets, Zhou et al. used the structure of LeuT to predict mutations in the serotonin and dopamine transporters that would make them more sensitive to inhibition by desipramine. In contrast, Singh et al. note the sequence divergence between the mammalian and bacterial family members to suggest that the mammalian binding site for the antidepressants might differ in some details. This question may be resolved by future efforts at cocrystallizing tricyclic antidepressants with their mammalian targets. Other recent work on the family of sodium neurotransmitter cotranporters by Forrest et al. (2007) and Zomot et al. (2007) explores why many of the mammalian members of the family depend on chloride …