1. Deacetylation as a receptor-regulated direct activation switch for pannexin channels.
- Author
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Chiu YH, Medina CB, Doyle CA, Zhou M, Narahari AK, Sandilos JK, Gonye EC, Gao HY, Guo SY, Parlak M, Lorenz UM, Conrads TP, Desai BN, Ravichandran KS, and Bayliss DA
- Subjects
- Acetylation, Animals, Cells, Cultured, Connexins genetics, Connexins physiology, HEK293 Cells, Histone Deacetylase 6 genetics, Humans, Jurkat Cells, Lysine genetics, Lysine metabolism, Membrane Potentials physiology, Mice, Inbred C57BL, Mice, Knockout, Nerve Tissue Proteins genetics, Nerve Tissue Proteins physiology, Patch-Clamp Techniques, Receptors, Adrenergic, alpha-1 genetics, Signal Transduction genetics, rhoA GTP-Binding Protein genetics, rhoA GTP-Binding Protein metabolism, Mice, Connexins metabolism, Histone Deacetylase 6 metabolism, Nerve Tissue Proteins metabolism, Receptors, Adrenergic, alpha-1 metabolism
- Abstract
Activation of Pannexin 1 (PANX1) ion channels causes release of intercellular signaling molecules in a variety of (patho)physiological contexts. PANX1 can be activated by G protein-coupled receptors (GPCRs), including α1-adrenergic receptors (α1-ARs), but how receptor engagement leads to channel opening remains unclear. Here, we show that GPCR-mediated PANX1 activation can occur via channel deacetylation. We find that α1-AR-mediated activation of PANX1 channels requires Gαq but is independent of phospholipase C or intracellular calcium. Instead, α1-AR-mediated PANX1 activation involves RhoA, mammalian diaphanous (mDia)-related formin, and a cytosolic lysine deacetylase activated by mDia - histone deacetylase 6. HDAC6 associates with PANX1 and activates PANX1 channels, even in excised membrane patches, suggesting direct deacetylation of PANX1. Substitution of basally-acetylated intracellular lysine residues identified on PANX1 by mass spectrometry either prevents HDAC6-mediated activation (K140/409Q) or renders the channels constitutively active (K140R). These data define a non-canonical RhoA-mDia-HDAC6 signaling pathway for GαqPCR activation of PANX1 channels and uncover lysine acetylation-deacetylation as an ion channel silencing-activation mechanism., (© 2021. The Author(s).)
- Published
- 2021
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