Subtype-selective conopeptides targeted to nicotinic receptors:Concerted discovery and biomedical applications

Abstract

Conus peptides that are selectively targeted to different molecular isoforms of nicotinic acetylcholine receptors (nAChRs) have been identified and characterized; several have recently been shown to have significant biomedical potential. An emerging strategy for the discovery from animal biodiversity of subtype-specific ligands for ion channel families is described in this review. Characterization of the gene family encoding a set of related ligands is required for discovery using a molecular genetics approach; when discovery is guided by a knowledge of the phylogeny of the biodiverse animal lineage being used as a source of ligands, a rational, efficient scan of the library of putative ligands becomes feasible. Together, these constitute an approach to uncover subtype-specific ligands, called "concerted discovery"; this was applied to the α-conotoxins, a family of Conus peptides generally targeted to nAChRs.Subtype-specific α-conotoxins were developed that target two groups of nAChRs, α 6 * and α 9 *. α-conotoxin MII has become the defining ligand for identifying the α 6 * nAChR subtype. A synthetic analog, MII [E11A], further subdivides α 6 * nAChRs into those that contain an α 4 subunit and those that do not. Importantly, these two subtypes are differentially affected by nigrostriatal damage, findings of likely relevance to the pathopysiology of Parkinson's disease. In contrast, α-conotoxins that target α 9 nAChR subtypes have potential as analgesics for the treatment of neuropathic pain that develops after nerve injury. The discovery of α-conotoxin RgIA enabled the identification of a novel role for α 9 * nAChRs. Use of α 9 * nAChR antagonists is associated with reversal of inflammation caused by the nerve injury. Thus, subtype-specific α-conotoxins targeted to particular nAChR isoforms are not only useful for understanding the physiological role of these receptors, but can have important diagnostic and therapeutic applications as well. Note: *Denotes the possible presence of additional subunits in the nAChR complex.

Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain

“…The α-conotoxins represent one such family that specifically target nicotinic acetylcholine receptor (nAChR) subtypes. Owing to the combination of a large variety of nAChR subunit assemblies and subunit-selective α-conotoxins, many potential novel analgesics have recently been identified (Dutton and Craik 2001;Alonso et al 2003;Sandall et al 2003;Lang et al 2005;Satkunanathan et al 2005;Olivera et al 2008;McIntosh et al 2009) α-Conotoxins, including Vc1.1, RgIA, MII and AuIB, have all been reported to potently reverse signs of neuropathic pain, particularly tactile allodynia, in animal models when administered systemically (Satkunanathan et al 2005;Klimis et al 2011).…”

Functional Characterization of α9-Containing Cholinergic Nicotinic Receptors in the Rat Adrenal Medulla: Implication in Stress-Induced Functional Plasticity

“…To address the functional role of ␣9-containing nAChRs in the adrenomedullary tissue, we took advantage of its potent and selective blockade by the ␣-conotoxin RgIA (␣-RgIA) Vincler et al, 2006;Olivera et al, 2008;Pérez et al, 2009). Our results obtained in rat acute adrenal slices show that ␣9-containing nAChRs are involved in the excitatory neurotransmission at the splanchnic nerve-chromaffin cell synapse and in the tonic inhibitory control exerted by cholinergic activity on gap junctional coupling.…”

Conotoxins: from the biodiversity of gastropods to new drugs

“…Очевидно общий физиологический эффект конотоксинов, ингибирующих постсинаптические рецепторы, заключается в нарушении нервно-мышечной передачи и, в конечном итоге, приводит к параличу жертвы [107]. По этому механизму действуют все ингибиторы никотиновых ацетилхолиновых рецепторов нервно-мышечного типа (nAChR), количественно доминирующие в яде рыбоядных видов рода Conus.…”

“…Среди a-конотоксинов обнаружены ингибиторы всех классов никотин-чувствительных рецепторов, описанных выше [107]. Некоторые подсемейства a-конотоксинов распространены только в пределах групп близкородственных видов рода Conus -примером может служить подсемейство конотоксинов a-3/5, являющееся основным ядом рыбоядных конусов группы Pionoconus [27].…”