Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of action potentials in neurons. The human genome includes ten human VGSC α-subunit genes, SCN(X)A, encoding Na1.1-1.9 plus Na. To understand the unique role that each VGSC plays in normal and pathophysiological function in neural networks, compounds with high affinity and selectivity for specific VGSC subtypes are required. Toward that goal, a structural analog of the VGSC pore blocker tetrodotoxin, 4,9-anhydrotetrodotoxin (4,9-ah-TTX), has been reported to be more selective in blocking Na current mediated by Na1.6 than other TTX-sensitive VGSCs, including Na1.2, Na1.3, Na1.4, and Na1.7. While SCN1A, encoding Na1.1, has been implicated in several neurological diseases, the effects of 4,9-ah-TTX on Na1.1-mediated Na current have not been tested. Here, we compared the binding of 4,9-ah-TTX for human and mouse brain preparations, and the effects of 4,9-ah-TTX on human Na1.1-, Na1.3- and Na1.6-mediated Na currents using the whole-cell patch clamp technique in heterologous cells. We show that, while 4,9-ah-TTX administration results in significant blockade of Na1.6-mediated Na current in the nanomolar range, it also has significant effects on Na1.1-mediated Na current. Thus, 4,9-ah-TTX is not a useful tool in identifying Na1.6-specific effects in human brain networks.
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| http://dx.doi.org/10.1016/j.neulet.2020.134853 | DOI Listing |
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