Endoplasmic Reticulum (ER)/Plasma Membrane (PM) Tethering Proteins E-Syts 1 and 2 Regulate Insertion and Function of ANO1 in the PM

Authors

• BA LeBlanc
• A Movahed Abtahi
• S Muallem
• WY Lin

Abstract

ANO1 (Anoctamin 1), a Ca2+-activated chloride channel and member of the anoctamin family, is regulated by Ca2+ and PI(4,5)P2. However, the role of tethering proteins in forming complexes of ANO1 and signaling in the specialized ER/PM junction where ANO1 is located is unknown. The regulation of ANO1 and potential interactions between these various molecules is a subject of which little has been uncovered, until now. IRBIT (Inositol 1,4,5-triphosphate receptor binding protein) serves a crucial intermediary role between IP3 and intracellular Ca2+ signaling pathways, inhibiting IP3 binding and the Ca2+ release channel. We discovered that IRBIT plays a further role promoting PM insertion of ANO1 and recruitment of ANO1 to ER/PM junctions and assembly of crucial ER/PM components. IRBIT acts with association of other tether proteins, in particular the ER localized VAPA and two of the three Extended synaptotagmins (E-Syts). VAPA targets all proteins possessing the FFAT motif to various membrane contact sites, including the ER/PM junctions. E-Syts are PM tether proteins anchored in the ER, each with a unique role regarding ANO1 regulation. IRBIT and VAPA specifically target E-Syt1 and E-Syt2 to the junctions to form selective complexes with the cAMP pathway; ANO1-VAPA-IRBIT-E-Syt1-AC8-AKAP3-PKA facilitate activation of ANO1 by Ca2+ and ANO1-VAPA-IRBIT-E-Syt2-AC6/3-AKAP11-PKA markedly reduce the affinity for activation of ANO1 by Ca2+. In addition, the complexes also increase or decrease, respectively, ANO1 cell surface expression. These opposing pathways present specific modes of regulation for ANO1 function, playing a major role in signal transduction and regulation of epithelial fluid and electrolyte secretion.

Scientific Focus Area: Systems Biology

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