TRUSS, TNF‐R1, and TRPC ion channels synergistically reverse endoplasmic reticulum Ca 2+ storage reduction in response to m1 muscarinic acetylcholine receptor signaling

• Published in: Journal of cellular physiology 2010-11, Vol.225 (2), p.444-453
• Main Authors: Mace, Kimberly E., Lussier, Marc P., Boulay, Guylain, Terry‐Powers, Jennifer L., Parfrey, Helen, Perraud, Anne‐Laure, Riches, David W.H.
• Format: Article
• Language: English
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.22221

Although most signaling responses initiated by tumor necrosis factor‐α (TNF‐α) occur in a Ca 2+ ‐independent fashion, TNF‐α receptor signaling augments Ca 2+ entry induced by Gα q/11 G‐protein coupled receptors (GPCRs) in endothelial cells and increases trans‐endothelial permeability. The signaling events involved in GPCR‐induced Ca 2+ influx have been characterized and involve store‐operated Ca 2+ entry facilitated by the Ca 2+ permeable ion channel, transient receptor potential canonical 4 (TRPC4). Little is known about the mechanisms by which TNF‐α receptor signaling augments GPCR‐induced Ca 2+ entry. T NF‐α R eceptor U biquitous S ignaling and S caffolding protein (TRUSS) is a tumor necrosis factor receptor‐1 (TNF‐R1)‐associated protein whose gene name is TRPC4‐associated protein (TRPC4AP). The goal of our study was to test the hypothesis that TRUSS serves to link TNF‐R1 and GPCR‐signaling pathways at the level of TRPC4 by: (i) determining if TRUSS and TNF‐R1 interact with TRPC4, and (ii) investigating the role of TRUSS, TNF‐R1, and TRPC4 in GPCR‐induced Ca 2+ signaling. Here, we show that TRUSS and TNF‐R1 interact with a sub‐family of TRPC channels (TRPC1, 4, and 5). In addition, we show that TRUSS and TNF‐R1 function together with TRPC4 to elevate endoplasmic reticulum Ca 2+ filling in the context of reduced endoplasmic reticulum Ca 2+ storage initiated by G‐protein coupled m1 muscarinic acetylcholine receptor (m1AchR) signaling. Together, these findings suggest that TNF‐R1, TRUSS, and TRPC4 augment Ca 2+ loading of endoplasmic reticulum Ca 2+ stores in the context of m1AchR stimulation and provide new insights into the mechanisms that connect TNF‐R1 to GPCR‐induced Ca 2+ signaling. J. Cell. Physiol. 225: 444–453, 2010. © 2010 Wiley‐Liss, Inc.