Linoleic acid induces opening of connexin26 hemichannels through a PI3K/Akt/Ca2+-dependent pathway

• Published in: Biochimica et biophysica acta. Biomembranes Vol. 1828; no. 3; pp. 1169 - 1179
• Main Authors: Figueroa, Vania, Sáez, Pablo J., Salas, José D., Salas, Daniela, Jara, Oscar, Martínez, Agustín D., Sáez, Juan C., Retamal, Mauricio A.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-03-2013
• Subjects: Cx26; Hearing loss; Hemichannel; Intracellular calcium; Polyunsaturated fatty acid; GJCs; Etd; Intracellular calcium; LA; DTT; Polyunsaturated fatty acid; HCs; Cx26; Hemichannel; Cxs; Hearing loss
• ISSN: 0005-2736; 1879-2642
• DOI: 10.1016/j.bbamem.2012.12.006

Connexin hemichannel (Cx HC) opening is involved in physiological and pathological processes, allowing the cellular release of autocrine/paracrine signaling molecules. Linoleic acid (LA) is known to modulate the functional state of connexin46 (Cx46) HCs. However, the molecular mechanism involved in this effect, or whether LA affects HCs constituted of other connexins, remains unknown. Here, we report the effects of LA on HCs in HeLa cells that express Cx26, one of the main Cxs in the cochlear sensory epithelium. Cx26 HC activity (dye uptake) was increased in a concentration-dependent manner by bath application of LA and inhibited by HC blockers. Moreover, intracellular BAPTA, a Ca2+ chelator, and PI3K/AKT inhibitors were found to reduce the LA-induced Cx26 HC opening, suggesting that the LA effect is mediated by an increase of free intracellular Ca2+ concentration and activation of the PI3K/Akt-dependent pathway. The LA-induced increase in free intracellular Ca2+ concentration was mainly due to Ca2+ influx through Cx26 HCs. In addition, the involvement of SH groups was ruled out, because dithiothreitol (DTT) did not block the LA-induced dye uptake. LA also increased the membrane current mediated by Cx26 HCs expressed in Xenopus oocytes and the dye uptake in HeLa cells expressing Cxs 32, 43 or 45. Since LA is an essential polyunsaturated fatty acid, its effect on HCs might be relevant to cell growth as well as to cellular functions of differentiated cells such as audition.
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► LA increases the activity of HCs formed by Cxs 26, 32, 43 and 45. ► LA induces a rise of intracellular free Ca2+ and activation of a PI3K/Akt-dependent pathway. ► Cx26 HCs mediate the Ca2+ influx to the cells in response to LA. ► Cx26 HCs are sensitive to a reducing environment.