title: Myristoylated alanine-rich C kinase substrate coordinates native TRPC1 channel activation by phosphatidylinositol 4,5-bisphosphate and protein kinase C in vascular smooth muscle.
abstract: Canonical transient receptor potential 1 (TRPC1) Ca(2+)-permeable cation channels contribute to vascular tone and blood vessel remodeling and represent potential therapeutic targets for cardiovascular disease. Protein kinase C (PKC) and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] are obligatory for native TRPC1 channel activation in vascular smooth muscle cells (VSMCs) but how PKC and PI(4,5)P2 act together to induce channel gating remains unresolved. The present study reveals that myristoylated alanine-rich C kinase substrate (MARCKS) protein coordinates activation of TRPC1 channels by PKC and PI(4,5)P2. TRPC1 channels and MARCKS form signaling complexes with PI(4,5)P2 bound to MARCKS; in this configuration TRPC1 channels are closed. Activators of TRPC1 channels induce PKC phosphorylation of TRPC1 proteins, which causes dissociation of TRPC1 subunits from MARCKS and release of PI(4,5)P2 from MARCKS; PI(4,5)P2 subsequently binds to TRPC1 subunits to induce channel opening. Calmodulin acting at, or upstream of, MARCKS is also required for TRPC1 channel opening through a similar gating mechanism involving PKC and PI(4,5)P2. These novel findings show that MARCKS coordinates native TRPC1 channel activation in VSMCs by acting as a reversible PI(4,5)P2 buffer, which is regulated by PKC-mediated TRPC1 phosphorylation. Moreover, our data provide evidence that PI(4,5)P2 is a gating ligand of TRPC1 channels.
authors.affiliation: 1Pharmacology and Cell Physiology, Division of Biomedical Sciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK. aalbert@sgul.ac.uk.
authors.forename: Jian
authors.initials: J
authors.lastname: Shi
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: William A
authors.initials: WA
authors.lastname: Large
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Albert
mesh_terms: D000818:Animals; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D011817:Rabbits; D050052:TRPC Cation Channels / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D011493:Protein Kinase C
keywords: Ca2+ signaling; calmodulin; transgenic
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