Allosteric modulators of solute carrier function: a theoretical framework.

Large-scale drug screening is currently the basis for the identification of new chemical entities. This is a rather laborious approach, because a large number of compounds must be tested to cover the chemical space in an unbiased fashion. However, the structures of targetable proteins have become increasingly available. Thus, a new era has arguably been ushered in with the advent of methods, which allow for structure-based docking campaigns (i.e., virtual screens). Solute carriers (SLCs) are among the most promising drug targets. This claim is substantiated by the fact that a large fraction of the 400 solute carrier genes is associated with human diseases. The ability to dock large ligand libraries into selected structures of solute carriers has set the stage for rational drug design. In the present study, we show that these structure-based approaches can be refined by taking into account how solute carriers operate. We specifically address the feasibility of targeting solute carriers with allosteric modulators, because their actions differ fundamentally from those of ligands, which bind to the substrate binding site. For the pertinent analysis we used transition state theory in conjunction with the linear free energy relationship (LFER). These provide the theoretical framework to understand how allosteric modulators affect solute carrier function.

Color-changing and color-tunable photonic bandgap fiber textiles.

We present the fabrication and use of plastic Photonic Band Gap Bragg fibers in photonic textiles for applications in interactive cloths, sensing fabrics, signage and art. In their cross section Bragg fibers feature periodic sequence of layers of two distinct plastics. Under ambient illumination the fibers appear colored due to optical interference in their microstructure. Importantly, no dyes or colorants are used in fabrication of such fibers, thus making the fibers resistant to color fading. Additionally, Bragg fibers guide light in the low refractive index core by photonic bandgap effect, while uniformly emitting a portion of guided color without the need of mechanical perturbations such as surface corrugation or microbending, thus making such fibers mechanically superior to the standard light emitting fibers. Intensity of side emission is controlled by varying the number of layers in a Bragg reflector. Under white light illumination, emitted color is very stable over time as it is defined by the fiber geometry rather than by spectral content of the light source. Moreover, Bragg fibers can be designed to reflect one color when side illuminated, and to emit another color while transmitting the light. By controlling the relative intensities of the ambient and guided light the overall fiber color can be varied, thus enabling passive color changing textiles. Additionally, by stretching a PBG Bragg fiber, its guided and reflected colors change proportionally to the amount of stretching, thus enabling visually interactive and sensing textiles responsive to the mechanical influence. Finally, we argue that plastic Bragg fibers offer economical solution demanded by textile applications.

Modulation of transmitter release via presynaptic ligand-gated ion channels.

Neurons communicate through the exocytotic release of transmitters from presynaptic axon terminals and the ensuing activation of postsynaptic receptors. Instantaneous responses of postsynaptic cells to released neurotransmitters are mediated by ligand-gated ion channels, whereas G protein-coupled receptors mediate rather delayed effects. Moreover, the actions of ionotropic receptors are transient (milliseconds to seconds) and those of G protein-coupled receptors are more long lasting (seconds to minutes). Accordingly, neuronal signalling via ligand-gated ion channels is termed neurotransmission, whereas signalling via G protein-coupled receptors is termed neuromodulation. Exocytotic transmitter release is modulated by a variety of mechanisms such as previous activity at the synapse and the presence of extracellular neurotransmitters. Like the postsynaptic responses, presynaptic modulation is not only mediated by slowly acting G protein-coupled receptors, but also by fast acting ligand-gated ion channels. Accordingly, members of all known families of ligand-gated ion channels (cys-loop receptors, such as GABA(A), glycine, nicotinic acetylcholine, and 5-HT(3) receptors, ionotropic glutamate receptors, P2X receptors, and vanilloid receptors) are known to control transmitter release. All these ligand-gated ion channels display heterogeneous structures and functions. Therefore, activation of such presynaptic receptors can control transmitter release in different ways and through a multitude of mechanisms. This review provides a summary of the functions of the different presynaptic ligand-gated ion channels and presents prototypic examples for the physiological and pharmacological relevance of these presynaptic receptors.