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Biphasic effect of linoleic acid on connexin 46 hemichannels

  • Ion Channels, Receptors and Transporters
  • Published:
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Abstract

Connexins form hemichannels at undocked plasma membranes and gap-junction channels (GJCs) at intercellular contacting zones. Under physiological conditions, hemichannels have low open probabilities, but their activation under pathological conditions, such as ischemia, induces and/or accelerates cell death. Connexin 46 (Cx46) is a major connexin of the lens, and mutations of this connexin induce cataracts. Here, we report the effects of linoleic acid (LA) on the electrical properties of Cx46 GJCs and hemichannels expressed in Xenopus laevis oocytes. LA has a biphasic effect, increasing hemichannel current at 0.1 μM and decreasing it at concentrations of 100 μM or higher. The effects of extracellular and microinjected LA conjugated to coenzyme A (LA-CoA) suggest that the current activation site is accessible from the intracellular but not extracellular compartment, whereas the current inhibitory site is either located in a region of the hemichannel pore inaccessible to intracellular LA-CoA, or requires crossing of LA through an organelle membrane. Experiments with other fatty acids demonstrated that the block of hemichannels depends on the presence of a hydrogenated double bond at position 9 and is directly proportional to the number of double bonds. Experiments in paired oocytes expressing Cx46 showed that LA does not affect GJCs. The block by unsaturated fatty acids reported here opens the possibility that increases in the concentration of these lipids in the lens induce cataract formation by blocking Cx46 hemichannels.

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Acknowledgments

This work was supported by the National Institutes of Health grants GM068586, GM79629, and R01GM079629-03S1; Texas Advanced Research Program grant 010674-0046-2007; Fondecyt de Iniciación 11080061; and Proyecto Interno Universidad del Desarrollo 23.400.012.

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Authors and Affiliations

  1. Laboratorio de Fisiología, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Avenida Las Condes 12438, Santiago, Chile

    Mauricio A. Retamal, Flavio Evangelista-Martínez & Carmen G. León-Paravic

  2. Department of Cell Physiology and Molecular Biophysics and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, 79430-6551, USA

    Mauricio A. Retamal, Guillermo A. Altenberg & Luis Reuss

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  1. Mauricio A. Retamal
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  2. Flavio Evangelista-Martínez
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  5. Luis Reuss
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Correspondence to Mauricio A. Retamal.

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Retamal, M.A., Evangelista-Martínez, F., León-Paravic, C.G. et al. Biphasic effect of linoleic acid on connexin 46 hemichannels. Pflugers Arch - Eur J Physiol 461, 635–643 (2011). https://doi.org/10.1007/s00424-011-0936-3

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  • DOI: https://doi.org/10.1007/s00424-011-0936-3

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