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Investigation into the role of an extracellular loop in mediating proton-evoked inhibition of voltage-gated sodium channels

Harms, E, Stoetzer, C, Stueber, T, O'Reilly, AO and Leffler, A (2017) Investigation into the role of an extracellular loop in mediating proton-evoked inhibition of voltage-gated sodium channels. Neuroscience Letters, 661. pp. 5-10. ISSN 0304-3940

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Abstract

Proton-evoked activation of sensory neurons is counteracted by inhibition of voltage-gated Na+ channels, and the low acid-sensitivity of sensory neuron of the African naked mole-rat (ANMr) was reported to be due to a strong proton-evoked block of ANMrNav1.7. Here we aimed to reevaluate the role of the suggested negatively-charged motif in the ANMrNav1.7 domain IV P-loop for inhibition by protons. Patch clamp recordings were performed on the recombinant α-subunits Nav1.2–1.8. The insertion of the negatively charged motif (EKE) of ANMrNav1.7 into human Nav1.7 results in an increased proton-evoked tonic inhibition, but also in a reduced channel function. While the voltage-dependency of fast inactivation is changed in hNav1.7-EKE, pH 6.4 fails to induce a significant shift in both constructs. Proton-evoked inhibition of other channel α-subunits reveals a discrete differential inhibition among α-subunits with hNav1.7 displaying the lowest proton-sensitivity. The mutant hNav1.7-EKE displays a similar proton-sensitivity as Nav1.2, Nav1.3, Nav1.6 and Nav1.8. Overall, a correlation between proton-evoked inhibition and motif charge was not evident. Accordingly, a homology model of hNav1.7 shows that the EKE motif residues do not contribute to the pore lumen. Our data confirms that a negative charge of a postulated proton-motif encodes for a high proton-sensitivity when inserted into hNav1.7. However, a negatively charged motif is not a reliable predictor for a high proton-sensitivity in other α-subunits. Given the distance of the proton-motif from the pore mouth it seems unlikely that a blocking mechanism involving direct obstruction of the pore underlies the observed proton-evoked channel inhibition.

Item Type: Article
Uncontrolled Keywords: 1109 Neurosciences, 1702 Cognitive Science, 1701 Psychology
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions: Natural Sciences and Psychology
Publisher: Elsevier
Related URLs:
Date Deposited: 25 Sep 2018 10:28
Last Modified: 25 Sep 2018 10:34
DOI or Identification number: 10.1016/j.neulet.2017.09.039
URI: http://researchonline.ljmu.ac.uk/id/eprint/9324

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