In addition to structure-guided modulator discovery, another promising approach for gaining control of a particular channel is the use of tethered ligands, in which covalent tethering

provides specificity and high local concentration to overcome a lack of ligand selectivity and low affinity (Erlanson et al., 2004). A variant of this approach that is particularly suited to the study of the nervous system is the photoswitched-tethered ligand. In this case, the linker connecting the active moiety to the protein can be rapidly and reversibly photoisomerized Luminespib cell line using two wavelengths of light to alternatively present ligand to its binding site and remove it and thereby activate or antagonize channels or block their pores (Szobota and Isacoff, 2010). Another promising strategy would be to engineer channels to respond to nonnative and normally inert ligands (Shapiro et al., 2012), as has been done in the so-called RASSL and DREADD G protein-coupled receptors (Alexander et al., 2009 and Pei et al.,

2008). The attraction of these latter methods is that they can bring the precision of studies that have been carried out in nonneuronal find more cells in Neuron’s first 25 years to the natural world of supermolecular complexes in neurons and within the intact neural circuits in vivo. The answer, then, to the question, “Is there anything

left to learn?” is a resounding “Yes!!!” There remain many critical issues of basic mechanism that need to be sorted out for many channel classes. The exciting thing for the coming quarter century is that channelologists will have an ever-increasing ability Sitaxentan to move from approaching channels as macromolecules to channels as biological entities. Making such connections should take us closer to the dream of understanding the function of the most complex device of all driven by life’s spark: the human brain. We thank B. Hille and W.A. Catterall for assistance with the figures and K. Brejc for critical comments on the manuscript. We thank Francesco Tombola for helpful discussion. This work was supported by grants to D.L.M. from NIH R01-HL080050, R01-DC007664, R01-MH093603, and U54-GM094625 to E.Y.I. from NIH R01 NS35549, and to L.Y.J. from NIH R37MH065334, R01NS069229, and the Howard Hughes Medical Institute. “
“Arguably, Emil du Bois-Reymond (1818–1896) initiated modern neuroscience with the discovery of the action potential and of chemical synaptic transmission at the neuromuscular junction.