Significance Voltage-gated sodium (Na v ) channels contribute to physiological and pathophysiological electrical signaling in nerve and muscle cells. Because Na v channel isoforms exhibit tissue-specific expression, subtype selective modulation of this channel family provides important drug development opportunities. However, most available Na v channel modulators are unable to distinguish between Na v channel subtypes, which limits their therapeutic utility because of cardiac or nervous system toxicity. This study describes a new class of subtype selective Na v channel inhibitors that interact with a region of the channel that controls voltage sensitivity. This interaction site may enable development of selective therapeutic interventions with reduced potential for toxicity.

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7’s role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission.

The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. Abstract:The resonant attachment of a free electron to a closed shell neutral molecule, and the interplay between the following electron detachment and electronic relaxation channels represents a fundamental but common process throughout chemical and biochemical systems. The new methodology of anion frequency-resolved photoelectron imaging is detailed and used to map-out molecular excited state dynamics of gas-phase para-benzoquinone, which is the electron accepting moiety in many biological electron-transfer chains. Three-dimensional spectra of excitation energy, electron kinetic energy and electron ejection anisotropy reveal clear fingerprints of excited and intermediate state dynamics. The results show that many of the excited states are strongly coupled, providing a route to forming the ground state radical anion, despite the fact that the electron is formally unbound in the excited states. The relation of our method to electron impact attachment studies and the key advantages, including the extension to time-resolved dynamics and to larger molecular systems is discussed.

The electronic energy and dynamics of solvated electrons, the simplest yet elusive chemical species, is of interest in chemistry, physics, and biology. Here, we present the electron binding energy distributions of solvated electrons in liquid water, methanol, and ethanol accurately measured using extreme ultraviolet (EUV) photoelectron spectroscopy of liquids with a single-order high harmonic. The distributions are Gaussian in all cases. Using the EUV and UV photoelectron spectra of solvated electrons, we succeeded in retrieving sharp electron kinetic energy distributions from the spectra broadened and energy shifted by inelastic scattering in liquids, overcoming an obstacle in ultrafast UV photoelectron spectroscopy of liquids. The method is demonstrated for the benchmark systems of charge transfer to solvent reaction and ultrafast internal conversion of hydrated electron from the first excited state.

Frequency-, angle-, and time-resolved photoelectron imaging of gas-phase menadione (vitamin K3) radical anions is used to show that quasi-bound resonances of the anion can act as efficient doorway states to produce metastable ground electronic state anions on a sub-picosecond timescale.

. (2015) 'Excited state dynamics of the isolated green uorescent protein chromophore anion following UV excitation.', Journal of physical chemistry B., 119 (10). pp. 3982-3987. Further information on publisher's website:http://dx.doi.org/10.1021/acs.jpcb.5b01432Publisher's copyright statement:This document is the Accepted Manuscript version of a Published Work that appeared in nal form in The Journal of Physical Chemistry B, copyright c American Chemical Society after peer review and technical editing by the publisher. To access the nal edited and published work see http://dx.doi.org/10.1021/acs.jpcb.5b01432. Additional information:Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details.

Publisher's copyright statement:This document is the Accepted Manuscript version of a Published Work that appeared in nal form in The Journal of Physical Chemistry Letters, copyright c American Chemical Society after peer review and technical editing by the publisher. To access the nal edited and published work see http://pubs.acs.org/doi/abs/10.1021/jz500264c. Additional information:Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. AbstractThe intrinsic photo-physics of nucleobases and nucleotides following UV absorption presents a key reductionist step towards understanding the complex photo-damage mechanisms occurring in DNA. Adenine in particular has been the focus of intense investigation, where there has been a long-standing uncertainty about the mechanism and how the dynamics of adenine correlate to those of its more biologically relevant nucleotide and oligonucleotides in aqueous solution. Here we report on time-resolved photoelectron imaging of the deprotonated 3'-deoxyadenosine-5'-monophosphate nucleotide and the adenosine di-and tri-nucleotides. Through a comparison of gas and solution phase experiments and available theoretical studies, we show that the dynamics of the base are insensitive to the surrounding environment and that the decay of the adenine base within a nucleotide probably involves internal conversion from the initially populated 1 ππ* states. This is in agreement with some recent theoretical studies. The relaxation dynamics of the adenosine oligonucleotides are very similar to those of the nucleobase, in contrast to the aqueous the oligonucleotides, where a fraction of the ensemble forms long-lived excimer states that are delocalised over two bases. 3The absorption of ultraviolet (UV) radiation by DNA can lead to biological damage including strand breaks and mutations that can ultimately lead to photolesions, transcription errors and cancer. 1 Despite the efficient UV absorption, mediated by the optically bright 1 ππ* states localised on the four DNA nucleobases, the photodamage quantum yield in DNA is low (<1%). 2,3 This photostability is governed by the non-radiative decay mechanisms that enable the nucleobases to assimilate and dispose of the potentially harmful electronic energy in a non-destructive fashion.Gaining a molecular level understanding of these processes has been a long-standing goal, not only because of its role in radiation damage of DNA, but also to assess why nature has evolved using such a select number of molecular building blocks to define the genetic code. 4 Much of the expe...

Formation and mode-specific autodetachment from a dipole-bound state in a radical anion dimer is observed in the frequency and time-domains.