A New α-Conotoxin Which Targets α3β2 Nicotinic Acetylcholine Receptors

Cartier, G. Edward; Yoshikami, Doju; Gray, William R.; Luo, Siqin; Olivera, Baldomero M.; McIntosh, J. Michael

doi:10.1074/jbc.271.13.7522

Cited by 468 publications

(535 citation statements)

References 32 publications

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“…Thus, nAChRs containing the ␣7 subunit do not appear to be required for wave generation. On the other hand, ␣-conotoxin-MII and ␣-conotoxin-AU1B, toxins that preferentially block ␣3␤2 and ␣3␤4 nAChRs, respectively (Cartier et al, 1996;Luo et al, 1998), dramatically reduced wave frequency. These findings indicate that the functional nAChR receptors mediating waves contain ␣3, ␤2, and ␤4 subunits.…”

Section: Nachr-mediated Retinal Wavesmentioning

confidence: 96%

The role of nAChR‐mediated spontaneous retinal activity in visual system development

Feller

2002

J. Neurobiol.

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ABSTRACT:In the developing vertebrate retina, nAChR synapses are among the first to appear. This early cholinergic circuitry plays a key role in generating "retinal waves," spontaneously generated waves of action potentials that sweep across the ganglion cell layer. These retinal waves exist for a short period of time during development when several circuits within the visual system are being established. Here I review the cholinergic circuitry of the developing retina and the role these early circuits play in the development of the retina itself and of retinal projections to the lateral geniculate nucleus of the thalamus.

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Section: Nachr-mediated Retinal Wavesmentioning

confidence: 96%

The role of nAChR‐mediated spontaneous retinal activity in visual system development

Feller

2002

J. Neurobiol.

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“…The α-conotoxins Vc1.1, AuIB and MII were synthesised as previously described (Schnolzer et al 1992;Cartier et al 1996;Luo et al 1998;Clark et al 2006). Briefly, Boc solid phase chemistry was used to synthesise, deprotect and cleave from the resin all peptides as described (Schnolzer et al 1992).…”

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confidence: 99%

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

et al. 2012

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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

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“…These conclusions were conclusively confirmed by the finding that deleting the α7 subunit resulted in elimination of the [ 125 I]-α-bungarotoxin binding site [70] and that null mutation of either the α4 [71] [73,75,76,77,78,79] demonstrating that what is routinely referred to as high affinity nicotine binding sites should be referred to as high affinity agonist binding sites. A little more than 10 years ago, two new high affinity ligands were introduced to the field, radiolabeled epibatidine [80,81] and α-conotoxin MII (α-CtxMII) [82,83]. [ 3 H]-Epibatidine was originally described as being a very high affinity ligand that was useful, principally, for measuring α4β2* nAChRs [80,81] (* indicates possible additional subunits).…”

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confidence: 99%

“…Expression of nAChRs in Xenopus laevis has shown that α-CtxMII binds with high affinity to α3β2* nAChRs [82] and α6β2* nAChRs [33]. However, deletion of nAChR subunits clearly demonstrated that α6 is required to form those nAChRs that bind 125 I]-α-CtxMII with high affinity in dopaminergic neurons whereas α3 is not.…”

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confidence: 99%

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

Grady

Salminen

Laverty

et al. 2007

Biochemical Pharmacology

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This review summarizes studies that attempted to determine the subtypes of nicotinic acetylcholine receptors (nAChR) expressed in the dopaminergic nerve terminals in the mouse. A variety of experimental approaches has been necessary to reach current knowledge of these subtypes, including in situ hybridization, agonist and antagonist binding, function measured by neurotransmitter release from synaptosomal preparations, and immunoprecipitation by selective antibodies. Early developments that facilitated this effort include the radioactive labeling of selective binding agents, such as [ 125 I]-α-bungarotoxin and [ 3 H]-nicotine, advances in cloning the subunits, and expression and evaluation of function of combinations of subunits in Xenopus oocytes. The discovery of epibatidine and α-conotoxin MII (α-CtxMII), and the development of nAChR subunit null mutant mice have been invaluable in determining which nAChR subunits are important for expression and function in mice, as well as allowing validation of the specificity of subunit specific antibodies. These approaches have identified five nAChR subtypes of nAChR that are expressed on dopaminergic nerve terminals. Three of these contain the α6 subunit (α4α6β2β3, α6β2β3, α6β2) and bind α-CtxMII with high affinity. One of these three subtypes (α4α6β2β3) also has the highest sensitivity to nicotine of any native nAChR that has been studied, to date. The two subtypes that do not have high affinity for α-CtxMII (α4β2, α4α5β2) are somewhat more numerous than the α6* subtypes, but do bind nicotine with high affinity. Given that our first studies detected readily measured differences in sensitivity to agonists and antagonists among these five nAChR subtypes, it seems likely that subtype selective compounds could be developed that would allow therapeutic manipulation of diverse nAChRs that have been implicated in a number of human conditions. Alterations in nicotinic cholinergic receptor (nAChRs) number or function have been implicated in psychopathologies such as anxiety, attention deficit hyperactivity disorder, depression, schizophrenia (reviewed in [1,2,3]), at least one form of familial epilepsy [4], and Parkinson's and Alzheimer's diseases [5]. It is not particularly surprising that nAChRs might play important roles in modulating several human diseases given that binding sites for nicotinic ligands such as [ 125 I]-α-bungarotoxin [6,7,8], [ 3 H]-nicotine [7,8] Corresponding author: Sharon R Grady e-mail: sharon.grady@colorado.edu phone: 303-492-9677 fax: 303-492-8063 mailing address: Institute for Behavioral Genetics University of Colorado 447UCB Boulder, CO 80309. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered w...

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A New α-Conotoxin Which Targets α3β2 Nicotinic Acetylcholine Receptors

Cited by 468 publications

References 32 publications

The role of nAChR‐mediated spontaneous retinal activity in visual system development

The role of nAChR‐mediated spontaneous retinal activity in visual system development

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

The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum

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