Ion beam micromachining of integrated optics components

Thin film integrated optics components such as light guides, modulators, directional couplers, and polarizers demand high quality edge smoothness and high resolution pattern formation in dimensions down to submicrometer size. Fabrication techniques combining holographic and scanning electron beam lithography with ion beam micromachining have produced planar phase gratings with intervals as small as 2800 Å, guiding channel couplers in GaAs, and also wire- grid polarizers for 10.6-µm radiation

Design of novel ion channel modulators

Function and modulation of neuronal sodium channels are critical for the neuromodulation of electrical excitability and synaptic transmission in neurons - the basis for many aspects of signal transduction, learning, memory and physiological regulation. Mutations in neuronal voltage-gated sodium channel genes are responsible for various human neurological disorders. Furthermore, human neuronal voltage-gated sodium channels are primary targets of therapeutic drugs used as local anesthetics and for treatment of neurological and cardiac disorders. Yarov-Yarovoy\u27s lab is working on rational design of novel therapeutically useful blockers of voltage-gated sodium channels for treatment of pain and epilepsy. Serious, chronic pain affects at least 116 million Americans each year and epilepsy affects nearly 3 million Americans and 50 million people Worldwide. However, the treatment of chronic pain and epilepsy remains a major unmet medical need because the use of currently available drugs is limited due to incomplete efficacy and/or significant side effects. Considerable efforts by pharmaceutical industry toward identifying selective inhibitors of one or more of voltage-gated sodium channels subtypes did not generate any genuinely subtype selective blockers. Yarov-Yarovoy\u27s laboratory uses an innovative approach to design novel subtype selective voltage-gated sodium channel blocking peptides, small molecules, and antibodies. This project will provide key structural information on the molecular basis of neuronal voltage-gated sodium channels function and its interaction with therapeutically useful subtype-specific modulators

Planar lipid bilayers in recombinant ion channel research

There are a number of methods of investigating the function of recombinant proteins such as ion channels. However, after channel purification there are few methods to guarantee that the protein still functions. For ion channels, reconstituting back into planar lipid bilayers and demonstrating preserved function is a convenient and trusted method. It is cell free and even inaccessible, intracellular ion channels can be studied. We have used this method to study the function of recombinant channels of known subunit composition and have found it convenient for investigating the mode of action of ion channel modulators

Generation of Molecular Diversity from Amino Acids. A Source for the Discovery of New TRP Channel Modulators

Trabajo presentado en el IV RECI: New Horizons in Ion Channel Research, celebrado en Cuenca (España) del 12 al 13 de febrero de 2013.Ion channels are central and challenging targets in medicinal chemistry but, because of the scarce structural knowledge, rational approaches to ion channel modulators are still rare. Moreover, the multimodal activation of some channels, like TRPs, complicates still more the scenario for rational discovery programs. Due to these facts, most strategies directed to identify ion channel modulators rely on the screening of peptide and small-molecule libraries. In this context, we have been involved in the development of synthetic pathways for the generation of diverse, chiral, highly functionalized linear and heterocyclic scaffolds from amino acids, and in the production of discrete libraries from them. The screening of these libraries on different TRP channels has allowed the discovery of some innovative hits that have progressed to hit-to-lead optimization programs. This communication will deal with the synthesis, structural characterization, and biological evaluation of a collection of β,γ–diaminoester derivatives that display significant activity at TRPV1, TRPM8 and TRPA1 channels. Compound RGM04-7, a selective.Supported by MICINN grants: Consolider-Ingenio 2010 (CSD2008-00005 and CSD2006-00015), SAF2009-09323 and BFU2009-08346, and the Generalitat Valenciana (PROMETEO/2010/046)

Druggable lipid binding sites in pentameric ligand-gated ion channels and transient receptor potential channels

Lipids modulate the function of many ion channels, possibly through direct lipid-protein interactions. The recent outpouring of ion channel structures by cryo-EM has revealed many lipid binding sites. Whether these sites mediate lipid modulation of ion channel function is not firmly established in most cases. However, it is intriguing that many of these lipid binding sites are also known sites for other allosteric modulators or drugs, supporting the notion that lipids act as endogenous allosteric modulators through these sites. Here, we review such lipid-drug binding sites, focusing on pentameric ligand-gated ion channels and transient receptor potential channels. Notable examples include sites for phospholipids and sterols that are shared by anesthetics and vanilloids. We discuss some implications of lipid binding at these sites including the possibility that lipids can alter drug potency or that understanding protein-lipid interactions can guide drug design. Structures are only the first step toward understanding the mechanism of lipid modulation at these sites. Looking forward, we identify knowledge gaps in the field and approaches to address them. These include defining the effects of lipids on channel function in reconstituted systems using asymmetric membranes and measuring lipid binding affinities at specific sites using native mass spectrometry, fluorescence binding assays, and computational approaches

Development of the analog ASIC for multi-channel readout X-ray CCD camera

We report on the performance of an analog application-specific integrated circuit (ASIC) developed aiming for the front-end electronics of the X-ray CCDcamera system onboard the next X-ray astronomical satellite, ASTRO-H. It has four identical channels that simultaneously process the CCD signals. Distinctive capability of analog-to-digital conversion enables us to construct a CCD camera body that outputs only digital signals. As the result of the front-end electronics test, it works properly with low input noise of =<30 uV at the pixel rate below 100 kHz. The power consumption is sufficiently low of about 150 mW/chip. The input signal range of 720 mV covers the effective energy range of the typical X-ray photon counting CCD (up to 20 keV). The integrated non-linearity is 0.2% that is similar as those of the conventional CCDs in orbit. We also performed a radiation tolerance test against the total ionizing dose (TID) effect and the single event effect. The irradiation test using 60Co and proton beam showed that the ASIC has the sufficient tolerance against TID up to 200 krad, which absolutely exceeds the expected amount of dose during the period of operating in a low-inclination low-earth orbit. The irradiation of Fe ions with the fluence of 5.2x10^8 Ion/cm2 resulted in no single event latchup (SEL), although there were some possible single event upsets. The threshold against SEL is higher than 1.68 MeV cm^2/mg, which is sufficiently high enough that the SEL event should not be one of major causes of instrument downtime in orbit.Comment: 16 pages, 6 figure

Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer

TRPM8 ion channels, the primary cold sensors in humans, are activated by innocuous cooling (<28 °C) and cooling compounds (menthol, icilin) and are implicated in sensing unpleasant cold stimuli as well as in mammalian thermoregulation. Overexpression of these thermoregulators in prostate cancer and in other life-threatening tumors, along with their contribution to an increasing number of pathological conditions, opens a plethora of medicinal chemistry opportunities to develop receptor modulators. This Perspective seeks to describe current known modulators for this ion channel because both agonists and antagonists may be useful for the treatment of most TRPM8-mediated pathologies. We primarily focus on SAR data for the different families of compounds and the pharmacological properties of the most promising ligands. Furthermore, we also address the knowledge about the channel structure, although still in its infancy, and the role of the TRPM8 protein signalplex to channel function and dysfunction. We finally outline the potential future prospects of the challenging TRPM8 drug discovery fieldWe thank Gregorio Fernández-Ballester for the figure of the TRPM8 homology model. Funding from the Ministry of Economy and Competitiveness (BFU 2012-39092-C02; SAF2015-66275-C2-R) and the Generalitat Valenciana (PROMETEO II/2014/011).Peer reviewe

Drug targets: ligand and voltage gated ion channels

The elucidation of a drug target is one of the earliest and most important steps in the drug discovery process. Ion channels encompassing both the ligand gated and voltage gated types are the second most common drug targets after G-Protein Coupled Receptors (GPCR). Ion channels are basically pore forming membrane proteins specialized for conductance of ions as per the concentration gradient. They are further broadly classified based on the energy (ATP) dependence into active ion channels/pumps and passive ion channels. Gating is the regulatory mechanism of these ion channels by which binding of a specific molecule or alteration in membrane potential induces conformational change in the channel architecture to result in ion flow or its inhibition. Thus, the study of ligand and voltage gated ion channels becomes an important tool for drug discovery especially during the initial stage of target identification. This review aims to describe the ligand and voltage gated ion channels along with discussion on its subfamilies, channel architecture and key pharmacological modulators

Mechanism Of Allosteric Modulation Of The Cys-Loop Receptors

The cys-loop receptor family is a major family of neurotransmitter-operated ion channels. They play important roles in fast synaptic transmission, controlling neuronal excitability, and brain function. These receptors are allosteric proteins, in that binding of a neurotransmitter to its binding site remotely controls the channel function. The cys-loop receptors also are subject to allosteric modulation by many pharmaceutical agents and endogenous modulators. By binding to a site of the receptor distinct from the neurotransmitter binding site, allosteric modulators alter the response of the receptors to their agonists. The mechanism of allosteric modulation is traditionally believed to be that allosteric modulators directly change the binding affinity of receptors for their agonists. More recent studies support the notion that these allosteric modulators are very weak agonists or antagonists by themselves. They directly alter channel gating, and thus change the distribution of the receptor across multiple different affinity states, indirectly influencing receptors\u27 sensitivity to agonists. There are two major locations of allosteric modulator binding sites. One is in subunit interfaces of the amino-terminal domain. The other is in the transmembrane domain close to the channel gating machinery. In this review, we also give some examples of well characterized allosteric binding pockets. © 2010 by the authors