NDLI: A tryptophan residue (W736) in the amino-terminus of the P-segment of domain II is involved in pore formation in Nav1.4 voltage-gated sodium channels

Content Provider	Springer Nature Link
Author	Carbonneau, Eric Vijayaragavan, Kausalia Chahine, Mohamed
Copyright Year	2002
Abstract	Voltage-gated Na channels comprise four homologous domains each consisting of six transmembrane segments (S1–S6) linked by loops. The linkers between segments S5 and S6 in each domain (P-loops), denoted as SS1-SS2, form the pore of the channel. It is believed that the SS1 region of the P-loops dips into, while the SS2 region exits out of the membrane. We have reported previously that residues A728 and D730 (in SS1 of domain II) contribute to the external vestibule of the pore of the rat skeletal muscle Na channel (Nav1.4). In this study, we examined the role of a conserved neighbouring tryptophan residue at position 736 (W736) in the pore formation. The W736 residue of Nav1.4 was replaced by a cysteine using site-directed mutagenesis. Complementary RNAs encoding the wild-type and mutant channels were injected into Xenopus laevis oocytes and macroscopic Na+ currents measured using the two-microelectrode voltage-clamp technique. The W736C mutant showed increased channel sensitivity to externally applied Cd2+ and methanethiosulphonate-ethyltrimethylammonium (MTSET). Furthermore, micromolar concentrations of Cd2+ reduced single-channel current amplitude in the Nav1.4/W736C mutant without affecting its voltage dependence. However, only small differences in tetrodotoxin and µ-conotoxin GIIIA affinity were observed between the wild-type and mutant channels. Replacing Na+ with other cations – K+, Li+, Cs+ or NH4 + – did not change the ion permeation sequence of the Nav1.4/W736C mutant channel. The results suggest that W736 contributes to the formation of the pore, close to the mouth of the channel, but is not part of the selectivity filter.
Starting Page	18
Ending Page	24
Page Count	7
File Format	PDF
ISSN	00316768
Journal	Pflügers Archiv
Volume Number	445
Issue Number	1
e-ISSN	14322013
Language	English
Publisher	Springer-Verlag
Publisher Date	2002-08-14
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Clinical Biochemistry

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