The voltage-gated sodium channel inhibitor, 4,9-anhydrotetrodotoxin, blocks human Nav1.1 in addition to Nav1.6
| Autor: | Alexandra A. Bouza, Nicholas Denomme, Jacob M. Hull, April L. Lukowski, Margaret B. Jameson, Lori L. Isom, Alison R. H. Narayan |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Mice 129 Strain Heterologous Mice Transgenic Tetrodotoxin Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Species Specificity medicine Animals Humans Patch clamp Structural analog Voltage-Gated Sodium Channel Blockers Dose-Response Relationship Drug Chemistry General Neuroscience Sodium channel Human brain NAV1.1 Voltage-Gated Sodium Channel HEK293 Cells 030104 developmental biology medicine.anatomical_structure NAV1.6 Voltage-Gated Sodium Channel NAV1 Biophysics Female 030217 neurology & neurosurgery Function (biology) |
| Zdroj: | Neurosci Lett |
| ISSN: | 0304-3940 |
| DOI: | 10.1016/j.neulet.2020.134853 |
| Popis: | 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 Na(v)1.1–1.9 plus Na(x). 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 Na(v)1.6 than other TTX-sensitive VGSCs, including Na(v)1.2, Na(v)1.3, Na(v)1.4, and Na(v)1.7. While SCN1A, encoding Na(v)1.1, has been implicated in several neurological diseases, the effects of 4,9-ah-TTX on Na(v)1.1-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 Na(v)1.1-, Na(v)1.3- and Na(v)1.6-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 Na(v)1.6-mediated Na(+) current in the nanomolar range, it also has significant effects on Na(v)1.1-mediated Na(+) current. Thus, 4,9-ah-TTX is not a useful tool in identifying Na(v)1.6-specific effects in human brain networks. |
| Databáze: | OpenAIRE |
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