PMID:18230622

Citation	Otsuguro, K, Tang, J, Tang, Y, Xiao, R, Freichel, M, Tsvilovskyy, V, Ito, S, Flockerzi, V, Zhu, MX and Zholos, AV (2008) Isoform-specific inhibition of TRPC4 channel by phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. 283:10026-36
Abstract	Full-length transient receptor potential (TRP) cation channel TRPC4alpha and shorter TRPC4beta lacking 84 amino acids in the cytosolic C terminus are expressed in smooth muscle and endothelial cells where they regulate membrane potential and Ca(2+) influx. In common with other "classical" TRPCs, TRPC4 is activated by G(q)/phospholipase C-coupled receptors, but the underlying mechanism remains elusive. Little is also known about any isoform-specific channel regulation. Here we show that TRPC4alpha but not TRPC4beta was strongly inhibited by intracellularly applied phosphatidylinositol 4,5-bisphosphate (PIP(2)). In contrast, several other phosphoinositides (PI), including PI(3,4)P(2), PI(3,5)P(2), and PI(3,4,5)P(3), had no effect or even potentiated TRPC4alpha indicating that PIP(2) inhibits TRPC4alpha in a highly selective manner. We show that PIP(2) binds to the C terminus of TRPC4alpha but not that of TRPC4beta in vitro. Its inhibitory action was dependent on the association of TRPC4alpha with actin cytoskeleton as it was prevented by cytochalasin D treatment or by the deletion of the C-terminal PDZ-binding motif (Thr-Thr-Arg-Leu) that links TRPC4 to F-actin through the sodium-hydrogen exchanger regulatory factor and ezrin. PIP(2) breakdown appears to be a required step in TRPC4alpha channel activation as PIP(2) depletion alone was insufficient for channel opening, which additionally required Ca(2+) and pertussis toxin-sensitive G(i/o) proteins. Thus, TRPC4 channels integrate a variety of G-protein-dependent stimuli, including a PIP(2)/cytoskeleton dependence reminiscent of the TRPC4-like muscarinic agonist-activated cation channels in ileal myocytes.
Links	PubMed PMC2365920 Online version:10.1074/jbc.M707306200
Keywords	Actins/genetics; Actins/metabolism; Amino Acid Motifs/physiology; Animals; Calcium/metabolism; Cell Line; Cytochalasin D/pharmacology; Cytoskeleton/genetics; Cytoskeleton/metabolism; Endothelial Cells/metabolism; GTP-Binding Protein alpha Subunits, Gi-Go/genetics; GTP-Binding Protein alpha Subunits, Gi-Go/metabolism; GTP-Binding Protein alpha Subunits, Gq-G11/genetics; GTP-Binding Protein alpha Subunits, Gq-G11/metabolism; Humans; Ileum/metabolism; Membrane Potentials/drug effects; Membrane Potentials/physiology; Mice; Muscle Cells/metabolism; Muscle, Smooth/metabolism; Nucleic Acid Synthesis Inhibitors; Phosphatidylinositol 4,5-Diphosphate/pharmacology; Phosphatidylinositol Phosphates/pharmacology; Protein Binding/physiology; Protein Isoforms/antagonists & inhibitors; Protein Isoforms/genetics; Protein Isoforms/metabolism; Protein Structure, Tertiary/physiology; TRPC Cation Channels/antagonists & inhibitors; TRPC Cation Channels/genetics; TRPC Cation Channels/metabolism; Type C Phospholipases/genetics; Type C Phospholipases/metabolism
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