Title Molecular basis for potentiation of Cx36 gap junction channel conductance by n-alcohols and general anesthetics /
Authors Raškevičius, Vytautas ; Jotautis, Vaidas ; Rimkutė, Lina ; Marandykina, Alina ; Kazokaitė, Mintautė ; Kairys, Visvaldas ; Skeberdis, Vytenis Arvydas
DOI 10.1042/BSR20171323
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Is Part of Bioscience reports.. London : Portland Press on behalf of the Biochemical Society. 2018, vol. 38, no. 1, art. no. BSR20171323, p. 1-12.. ISSN 0144-8463. eISSN 1573-4935
Keywords [eng] Connexins ; Gap junctions ; Disulfides ; Isoflurane ; Hexanols
Abstract [eng] In our recent study, we have demonstrated that short carbon chain n -alcohols (up to octanol) stimulated while long carbon chain n -alcohols inhibited the conductance of connexin 36 (Cx36) gap junction (GJ) channels. In contrast, GJ channels composed of other types of Cxs all were inhibited by n -alcohols independently on their carbon chain length. To identify the putative structural domains of Cx36, responsible for the dual effect of n -alcohols, we performed structural modeling of Cx36 protein docking with hexanol and isoflurane that stimulated as well as nonanol and carbenoxolone that inhibited the conductance of Cx36 GJs and revealed their multiple common docking sites and a single pocket accessible only to hexanol and isoflurane. The pocket is located in the vicinity of three unique cysteine residues, namely C264 in the fourth, and C92 and C87 in the second transmembrane domain of the neighboring Cx36 subunits. To examine the hypothesis that disulfide bonding might be involved in the stimulatory effect of hexanol and isoflurane, we generated cysteine substitutions in Cx36 and demonstrated by a dual whole-cell patch-clamp technique that in HeLa and N2A cells these mutations reversed the stimulatory effect of hexanol and isoflurane to inhibitory one, typical of other Cxs that lack respective cysteines and a specific docking pocket for these compounds. Our findings suggest that the stimulatory effect of hexanol and isoflurane on Cx36 GJ conductance could be achieved by re-shuffling of the inter-subunit disulfide bond between C264 and C92 to the intra-subunit one between C264 and C87.
Published London : Portland Press on behalf of the Biochemical Society
Type Journal article
Language English
Publication date 2018