<i>Conus</i> Peptides Targeted to Specific Nicotinic Acetylcholine Receptor Subtypes

McIntosh, J. Michael; Santos, Ameurfina D.; Olivera, Baldomero M.

doi:10.1146/annurev.biochem.68.1.59

Cited by 293 publications

(287 citation statements)

References 88 publications

Supporting

Mentioning

280

Contrasting

Unclassified

Order By: Relevance

“…Vc1.1 and RgIA are both potent antagonists of α9α10 nAChRs, suggesting this may be the anti-allodynia target (Vincler et al 2006). However, MII and AuIB are both devoid of activity at α9α10 nAChRs (McIntosh et al 1999;Callaghan et al 2008;Azam and McIntosh 2009;Callaghan and Adams 2010;Klimis et al 2011) and other -conotoxin analogues that act on these nAChRs fail to inhibit allodynia (Nevin et al 2007). Moreover, 910 nAChRs show very limited tissue distribution, being expressed predominantly in the olivochochlear system (Vetter et al, 2007) and their role in sensory nerve function is unclear.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

The large diversity of peptides from venomous creatures with high affinity for molecules involved in the development and maintenance of neuropathic pain has led to a surge in venom-derived analgesic research. Some members of the α-conotoxin family from Conus snails which specifically target subtypes of nicotinic acetylcholine receptors (nAChR) have been shown to be effective at reducing mechanical allodynia in neuropathic pain models. We sought to determine if three such peptides, Vc1.1, AuIB and MII were effective following intrathecal administration in a rat neuropathic pain model because they exhibit different affinities for the major putative pain relieving targets of α-conotoxins. Intrathecal administration of α-conotoxins, Vc1.1, AuIB and MII into neuropathic rats reduced mechanical allodynia for up to 6 hours without significant side effects. In vitro patch-clamp electrophysiology of primary afferent synaptic transmission revealed the mode of action of these toxins was not via a GABA B -dependant mechanism, and is more likely related to their action at nAChRs containing combinations of α3, α7 or other subunits. Intrathecal nAChR subunitselective conotoxins are therefore promising tools for the effective treatment of neuropathic pain. AbstractThe large diversity of peptides from venomous creatures with high affinity for molecules involved in the development and maintenance of neuropathic pain has led to a surge in venom-derived analgesic research. Some members of the α-conotoxin family from Conus snails which specifically target subtypes of nicotinic acetylcholine receptors (nAChR) have been shown to be effective at reducing mechanical allodynia in neuropathic pain models. We sought to determine if three such peptides, Vc1.1, AuIB and MII were effective following intrathecal administration in a rat neuropathic pain model because they exhibit different affinities for the major putative pain relieving targets of α-conotoxins. Intrathecal administration of α-conotoxins, Vc1.1, AuIB and MII into neuropathic rats reduced mechanical allodynia for up to 6 hours without significant side effects. In vitro patch-clamp electrophysiology of primary afferent synaptic transmission revealed the mode of action of these toxins was not via a GABA B -dependant mechanism, and is more likely related to their action at nAChRs containing combinations of α3, α7 or other subunits. Intrathecal nAChR subunitselective conotoxins are therefore promising tools for the effective treatment of neuropathic pain.3

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

show abstract

“…These groups have different degrees of antagonistic effect on distinct nAChRs. The α4/7 subfamily, as well as the α4/3 and α4/4 subfamilies, targets neuronal nAChRs with one exception of α-EI [24,31]. Such a characteristic of the α4/7 subfamily differs from that of the α3/5 subfamily that mostly blocks neuromuscular α1β1γδ subtypes [24].…”

Section: Introductionmentioning

confidence: 99%

α4/7-conotoxin Lp1.1 is a novel antagonist of neuronal nicotinic acetylcholine receptors

et al. 2008

View full text Add to dashboard Cite

Cone snails comprise approximately 500 species of venomous molluscs which have evolved the ability to generate multiple toxins with varied and exquisite selectivity. α-Conotoxin is a powerful tool for defining the composition and function of nicotinic acetylcholine receptors which play a crucial role in excitatory neurotransmission and are important targets for drugs and insecticides. An α4/7 conotoxin, Lp1.1, originally identified by cDNA and genomic DNA cloning from Conus leopardus, was found devoid of the highly conserved Pro residue in the first intercysteine loop. To further study this toxin, α-Lp1.1 was chemically synthesized and refolded into its globular disulfide isomer. The synthetic Lp1.1 induced seizure and paralysis on freshwater goldfish and selectively reversibly inhibited ACh-evoked currents in Xenopus oocytes expressing rat α3β2 and α6α3β2 nAChRs. Comparing the distinct primary structure with other functionally related α-conotoxins could indicate structural features in Lp1.1 that may be associated with its unique receptor recognition profile.

show abstract

“…Accordingly, we have examined several members of the large family of conus snail toxins for selectivity to the Lymnaea, Aplysia and Bulinus binding proteins [11,[19][20][21]. Many toxins also show considerable selectivity for the three binding proteins (Table I) [22,23].…”

Section: Structural Determinants Of Specificitymentioning

confidence: 99%

Structure-guided drug design: Conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes

Taylor

Talley

Radić

et al. 2007

Biochemical Pharmacology

View full text Add to dashboard Cite

Neuronal nicotinic receptors, encoded by nine genes of the alpha and three of the beta type of subunits, and whose gene products assemble in distinct permutations as pentameric molecules, constitute a fertile area for structure-guided drug design. Design strategies are augmented by a wide variety of peptide, alkaloid and terpenoid toxins from various marine and terrestrial species that interact with nicotinic receptors. Also, acetylcholinebinding proteins from mollusks, as structural surrogates of the receptor that mimic its extracellular domain, provide atomic resolution templates for analysis of structure and response. Herein, we describe a structure-guided approach to nicotinic ligand design that employs crystallography of this protein as the basic template, but also takes into consideration the dynamic properties of the receptor molecules in their biological media. We present the crystallographic structures of several complexes of various agonists and antagonists that associate with the agonist site and can competitively block the action of acetylcholine. In so far as the extracellular domain is involved, we identify additional noncompetitive sites at those subunit interfaces where agonists do not preferentially bind. Ligand association at these interface sites may modulate receptor function. Ligand binding is also shown by solution-based spectroscopic and spectrometric methods to affect the dynamics of discrete domains of the receptor molecule. The surrogate receptor molecules can then be employed to design ligands selective for receptor subtype through the novel methods of freeze-frame, click chemistry that uses the very structure of the target molecule as a template for synthesis of the inhibitor.

show abstract

Conus Peptides Targeted to Specific Nicotinic Acetylcholine Receptor Subtypes

Cited by 293 publications

References 88 publications

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

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

α4/7-conotoxin Lp1.1 is a novel antagonist of neuronal nicotinic acetylcholine receptors

Structure-guided drug design: Conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes

Contact Info

Product

Resources

About