Table of Contents

December 2007; 7 (6)


Net Results

Significant Deciles


  • The neurotransmitter transporters belonging to the solute carrier 6 (SLC6) family, including the γ-aminobutyric acid (GAT), norepinephrine (NET), serotonin (SERT) and dopamine (DAT) transporters are extremely important drug targets of great clinical relevance. These Na+, Cl-dependent transporters primarily function following neurotransmission to reset neuronal signaling by transporting neurotransmitter out of the synapse and back into the pre-synaptic neuron. Recent studies have tracked down an elusive binding site for Cl that facilitates neurotransmitter transport using structural differences evident with bacterial family members (e.g., the Aquifex aeolicus leucine transporter LeuTAa) that lack Cl dependence. Additionally, the crystal structures of antidepressant-bound LeuTAa reveals a surprising mode of drug interaction that may have relevance for medication development. The study of sequence and structural divergence between LeuTAa and human SLC6 family transporters can thus inform us as to how and why neurotransmitter transporters evolved a reliance on extracellular Cl to propel the transport cycle; what residue changes and helical rearrangements give rise to recognition of different substrates; and how drugs such as antidepressants, cocaine, and amphetamines halt (or reverse) the transport process.

  • Drug interactions and drug specificity are core themes for the pharmacologist. The paper discussed in this Viewpoint exploits the former to attain the latter. How can one improve local anesthetics so that they block pain but permit normal sensation? QX-314 is a charged derivative of lidocaine without anesthetic activity because it cannot diffuse across the cell membrane to access the neuronal voltage-dependent sodium channel. Capsaicin is a selective activator of the TRPV1 channel, the localization of which is restricted to sensory C-fiber neurons involved in nociception. Because the large pore size of the activated TRPV1 allows passage of large cations such as QX-314, combined treatment with capsaicin and QX-314 puts QX-314 uniquely into that subclass of neurons mediating pain, thereby achieving sensational specificity.


  • The specific posttranslational modification of protein cysteine residues by the addition of the tripeptide glutathione is termed S-glutathionylation. This process is promoted by oxidative and nitrosative stress but also occurs in unstressed cells. Altered levels of S-glutathionylation in some proteins have been associated with numerous pathologies, many of which have been linked to redox stress in the endoplasmic reticulum (ER). Proper protein folding is dependent upon controlled redox conditions within the ER, and it seems that ER conditions can in turn affect rates of S-glutathionylation. This article seeks to bring together the ways through which these processes are interrelated and considers the implications of these interrelationships upon therapeutic approaches to disease.

  • The Food and Drug Administration (FDA) recently introduced the Exploratory Investigational New Drug Guidance to expedite the clinical evaluation of new therapeutic and imaging agents. Early clinical studies performed under the auspices of this guidance, so-called “Phase 0” trials, have been initiated at the National Cancer Institute to integrate qualified pharmacodynamic biomarker assays into first-in-human cancer clinical trials. The goal of this integration is to establish proof of concept at the earliest stage of drug development. Phase 0 trials do not offer any possibility of patient benefit; instead, intensive, real-time pharmacodynamic and pharmacokinetic analyses of tumor samples and/or surrogate tissues inform subsequent trials. Phase 0 studies do not replace formal Phase I drug safety testing and require a substantial investment of resources; however, they promise more rational selection of agents for further, large-scale development as well as the identification of potential therapeutic failures early in the development process.

Beyond the Bench