μ-Conotoxins that differentially block sodium channels Nav1.1 through 1.8 identify those responsible for action potentials in sciatic nerve

Voltage-gated sodium channels (VGSCs) are important for action potentials. There are seven major isoforms of the pore-forming and gate-bearing α-subunit (Na v 1) of VGSCs in mammalian neurons, and a given neuron can express more than one isoform. Five of the neuronal isoforms, Na v 1.1, 1.2, 1.3, 1....

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Published in:Proceedings of the National Academy of Sciences - PNAS 2011-06, Vol.108 (25), p.10302-10307
Main Authors: Wilson, Michael J., Yoshikami, Doju, Azam, Layla, Gajewiak, Joanna, Olivera, Baldomero M., Bulaj, Grzegorz, Zhang, Min-Min
Format: Article
Language:English
Subjects:
Action potentials
Action Potentials - physiology
Animals
Biochemistry
Biological Sciences
Conotoxins - metabolism
Neurons
Neurotoxins - metabolism
Oocytes
Oocytes - cytology
Oocytes - physiology
Patch-Clamp Techniques
Pharmacology
Protein isoforms
Protein Isoforms - metabolism
Rats
Sciatic nerve
Sciatic Nerve - physiology
Sensory neurons
Sodium Channel Blockers - metabolism
Sodium channels
Sodium Channels - metabolism
Toxins
Xenopus laevis
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Summary:Voltage-gated sodium channels (VGSCs) are important for action potentials. There are seven major isoforms of the pore-forming and gate-bearing α-subunit (Na v 1) of VGSCs in mammalian neurons, and a given neuron can express more than one isoform. Five of the neuronal isoforms, Na v 1.1, 1.2, 1.3, 1.6, and 1.7, are exquisitely sensitive to tetrodotoxin (TTX), and a functional differentiation of these presents a serious challenge. Here, we examined a panel of 11 μ-conopeptides for their ability to block rodent Na v 1.1 through 1.8 expressed in Xenopus oocytes. Although none blocked Na v 1.8, a TTX-resistant isoform, the resulting "activity matrix" revealed that the panel could readily discriminate between the members of all pair-wise combinations of the tested isoforms. To examine the identities of endogenous VGSCs, a subset of the panel was tested on A- and C-compound action potentials recorded from isolated preparations of rat sciatic nerve. The results show that the major subtypes in the corresponding A- and C-fibers were Na v 1.6 and 1.7, respectively. Ruled out as major players in both fiber types were Na v 1.1, 1.2, and 1.3. These results are consistent with immunohistochemical findings of others. To our awareness this is the first report describing a qualitative pharmacological survey of TTX-sensitive Na v 1 isoforms responsible for propagating action potentials in peripheral nerve. The panel of μ-conopeptides should be useful in identifying the functional contributions of Na v 1 isoforms in other preparations.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1107027108