TRUSS, TNF-R1, and TRPC ion channels synergistically reverse endoplasmic reticulum Ca2+ storage reduction in response to m1 muscarinic acetylcholine receptor signaling.
Although most signaling responses initiated by tumor necrosis factor-alpha (TNF-alpha) occur in a Ca(2+)-independent fashion, TNF-alpha receptor signaling augments Ca(2+) entry induced by Galpha(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-alpha receptor signaling augments GPCR-induced Ca(2+) entry. TNF-alpha Receptor Ubiquitous Signaling and Scaffolding 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.
Mace
Kimberly E
KE
Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA.
Lussier
Marc P
MP
Boulay
Guylain
G
Terry-Powers
Jennifer L
JL
Parfrey
Helen
H
Perraud
Anne-Laure
AL
Riches
David W H
DW
D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D010539:Permeability; D043643:Receptor, Muscarinic M1 / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*
D043643:Receptor, Muscarinic M1; D047888:Receptors, Tumor Necrosis Factor, Type I; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; C550321:TRPC4AP protein, human; D002118:Calcium
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