Subtype-selective conopeptides targeted to nicotinic receptors: Concerted discovery and biomedical applications.
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 alpha-conotoxins, a family of Conus peptides generally targeted to nAChRs. Subtype-specific alpha-conotoxins were developed that target two groups of nAChRs, alpha(6)* and alpha(9)*. alpha-conotoxin MII has become the defining ligand for identifying the alpha(6)* nAChR subtype. A synthetic analog, MII [E11A], further subdivides alpha(6)* nAChRs into those that contain an alpha(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, alpha-conotoxins that target alpha(9) nAChR subtypes have potential as analgesics for the treatment of neuropathic pain that develops after nerve injury. The discovery of alpha-conotoxin RgIA enabled the identification of a novel role for alpha(9)* nAChRs. Use of alpha(9)* nAChR antagonists is associated with reversal of inflammation caused by the nerve injury. Thus, subtype-specific alpha-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.
Olivera
Baldomero M
BM
Department of Biology, University of Utah, Salt Lake City, Utah 84132, USA.
Quik
Maryka
M
Vincler
Michelle
M
McIntosh
J Michael
JM
D000818:Animals; D020916:Conotoxins / Q000494:pharmacology*; D052078:Conus Snail; D016503:Drug Delivery Systems; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008024:Ligands; D010455:Peptides / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*
D020916:Conotoxins; D008024:Ligands; D010455:Peptides; D011978:Receptors, Nicotinic