Deacetylation as a receptor-regulated direct activation switch for pannexin channels

Yu-Hsin Chiu (), Christopher B. Medina, Catherine A. Doyle, Ming Zhou, Adishesh K. Narahari, Joanna K. Sandilos, Elizabeth C. Gonye, Hong-Yu Gao, Shih Yi Guo, Mahmut Parlak, Ulrike M. Lorenz, Thomas P. Conrads, Bimal N. Desai, Kodi S. Ravichandran and Douglas A. Bayliss ()
Additional contact information
Yu-Hsin Chiu: University of Virginia
Christopher B. Medina: University of Virginia
Catherine A. Doyle: University of Virginia
Ming Zhou: Inova Schar Cancer Institute
Adishesh K. Narahari: University of Virginia
Joanna K. Sandilos: University of Virginia
Elizabeth C. Gonye: University of Virginia
Hong-Yu Gao: National Tsing Hua University
Shih Yi Guo: National Tsing Hua University
Mahmut Parlak: University of Virginia
Ulrike M. Lorenz: University of Virginia
Thomas P. Conrads: Inova Schar Cancer Institute
Bimal N. Desai: University of Virginia
Kodi S. Ravichandran: University of Virginia
Douglas A. Bayliss: University of Virginia

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-24825-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24825-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-24825-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().