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Targeting ion channels involved in neuropathic pain with natural peptides

English title Targeting ion channels involved in neuropathic pain with natural peptides
Applicant Hogg Ronald Cameron
Number 113835
Funding scheme Project funding (Div. I-III)
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2006 - 30.09.2008
Approved amount 119'021.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Cellular Biology, Cytology

Keywords (4)

natural toxins; neuronal nicotinic acetylcholine receptors; structure function; pain TTX-resistant sodium channels

Lay Summary (English)

Lead
Lay summary
The aim of this project is to identify new selective ligands for ion channels involved in neuropathic pain. Nicotinic acetylcholine receptors(nAChRs) containing the ?5 subunit and TTX-resistant, voltage-sensitive sodium channels (VSSCs) Nav1.8, have been identified as important mediators of neuropathic pain. In order to understand the molecular mechanisms and ultimately treat this disabling condition there is a need for selective ligands for these ion channels. Presently, there are no ligands that allow us to discriminate between nAChRs containing the ?5 subunit and those that do not. Similarly, there are very few ligands, which allow us to investigate the contribution of Nav1.8 to the pain response at the functional level. Two classes of conotoxins, from marine snails of the genus Conus are inhibitors of these two classes of ion channel. ?-conotoxins inhibit nAChRs, and many of these short peptides selectively target receptor subtypes, whereas the ?-conotoxins target VSSCs. Conotoxins are short peptides, between 10-20 amino acids in length, they are easily synthesised and the solution structure is known for many of them. Moreover, many of these toxins have a conserved peptide backbone, with the projecting amino acid sidechains determining their pharmacology.
Their ease of synthesis facilitates the incorporation of mutations which, when used in structure function studies, provides an understanding of the parts of the molecule which are determinant for their function.
Incorporation of natural and unnatural amino acids can radically change the pharmacology of these peptides and represents an important step towards the rational design of new ligands. It has been estimated that <0.1% of conotoxins have been characterised pharmacologically, we will search for conopeptides that target ?5-containing nAChRS and Nav1.8 VSSCs, the structure function relationship of the interactions will be examined and these will provide new pharmacophores for ligand design. The activities of these peptides on the electrical properties of native ganglia will also be investigated.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
105248 Modulation and blockade of human neuronal nicotinic acetylcholine receptors by endogenous and exogenous proteins 01.10.2004 Project funding (Div. I-III)

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