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Neuroscience_topics
Neuroscience: CNS disease, pain, brain research, ion channels, synaptic transmission, channelopathies, neuronal network
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Scooped by Julien Hering, PhD
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Ligand action on sodium, potassium, and calcium channels: role of permeant ions

Ligand action on sodium, potassium, and calcium channels: role of permeant ions | Neuroscience_topics | Scoop.it

Ion channels are targets for many naturally occurring toxins and small-molecule drugs. Despite great progress in the X-ray crystallography of ion channels, we still do not have a complete understanding of the atomistic mechanisms of channel modulation by ligands. In particular, the importance of the simultaneous interaction of permeant ions with the ligand and the channel protein has not been the focus of much attention. Considering these interactions often allows one to rationalize the highly diverse experimental data within the framework of relatively simple structural models. This has been illustrated in earlier studies on the action of local anesthetics, sodium channel activators, as well as blockers of potassium and calcium channels. Here, we discuss the available data with a view to understanding the use-, voltage-, and current carrying cation-dependence of the ligand action, paradoxes in structure–activity relationships, and effects of mutations in these ion channels. (...) - by Zhorov BS & Tikhonov DB, Trends in Pharmacological Sciences, In Press, Available online 1 February 2013

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Scooped by Julien Hering, PhD
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Marked difference in saxitoxin and tetrodoxin affinity for the human nociceptive voltage-gated sodium channel (Nav1.7)

Human nociceptive voltage-gated sodium channel (Nav1.7), a target of significant interest for the development of antinociceptive agents, is blocked by low nanomolar concentrations of (−)-tetrodotoxin(TTX) but not (+)-saxitoxin (STX) and (+)-gonyautoxin-III (GTX-III). These findings question the long-accepted view that the 1.7 isoform is both tetrodotoxin– and saxitoxin-sensitive and identify the outer pore region of the channel as a possible target for the design of Nav1.7-selective inhibitors. Single- and double-point amino acid mutagenesis studies along with whole-cell electrophysiology recordings establish two domain III residues (T1398 and I1399), which occur as methionine and aspartate in other Nav isoforms, as critical determinants of STX and gonyautoxin-III binding affinity. An advanced homology model of the Nav pore region is used to provide a structural rationalization for these surprising results. - by Walker JR et al., PNAS October 30, 2012 vol. 109 no. 44 18102-18107

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