Peptide-Toxin Tools for Probing the Expression and Function of Fetal and Adult Subtypes of the Nicotinic Acetylcholine Receptor

Although the neuromuscular nicotinic acetylcholine receptor (nAChR) is one of the most intensively studied ion channels in the nervous system, the differential roles of fetal and adult subtypes of the nAChR under normal and pathological conditions are still incompletely defined. Until recently, no p...

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Bibliographic Details
Published in:Annals of the New York Academy of Sciences 2008-06, Vol.1132 (1), p.61-70
Main Authors: Teichert, Russell W., Garcia, Carmen C., Potian, Joseph G., Schmidt, James J., Witzemann, Veit, Olivera, Baldomero M., McArdle, Joseph J.
Format: Article
Language:English
Subjects:
acetylcholine receptor
adult nAChR
Aging - physiology
Animals
conotoxin
Conotoxins - pharmacology
Crotalid Venoms - pharmacology
Electrophysiology
fetal nAChR
Kinetics
nAChR
Oocytes - drug effects
Oocytes - metabolism
Patch-Clamp Techniques
Protein Binding
Protein Subunits - classification
Protein Subunits - genetics
Protein Subunits - metabolism
Receptors, Nicotinic - classification
Receptors, Nicotinic - genetics
Receptors, Nicotinic - metabolism
Waglerin
Xenopus laevis
αA-conotoxin
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Summary:Although the neuromuscular nicotinic acetylcholine receptor (nAChR) is one of the most intensively studied ion channels in the nervous system, the differential roles of fetal and adult subtypes of the nAChR under normal and pathological conditions are still incompletely defined. Until recently, no pharmacological tools distinguished between fetal and adult subtypes. Waglerin toxins (from snake venom) and αAS‐conotoxins (from cone‐snail venom) have provided such tools. Because these peptides were characterized by different research groups using different methods, we have: 1) more extensively tested their subtype selectivity, and 2) begun to explore how these peptides may be used in concert to elucidate expression patterns and functions of fetal and adult nAChRs. In heterologous expression systems and native tissues, Waglerin‐1 and an αAS‐conotoxin analog, αA‐OIVA[K15N], are high‐affinity, highly selective inhibitors of the adult and fetal muscle nAChRs, respectively. We have used the peptides and their fluorescent derivatives to explore the expression and function of the fetal and adult nAChR subtypes. While fluorescent derivatives of these peptides indicated a gradual transition from fetal to adult muscle nAChRs in mice during the first 2 weeks postnatal, we unexpectedly observed a steeper transition in functional expression in the mouse diaphragm muscle using electrophysiology. As a toolkit of pharmacological agents with complementary specificity, αA‐OIVA[K15N] and Waglerin‐1 should have further utility in determining the roles of fetal and adult nAChR subtypes in development, in mature tissues, and under pathological conditions.
ISSN:0077-8923
1749-6632
DOI:10.1196/annals.1405.015