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Myristoylated alanine‐rich C kinase substrate coordinates native TRPC1 channel activation by phosphatidylinositol 4,5‐bisphosphate and protein kinase C in vascular smooth muscle
Author(s) -
Shi Jian,
Birnbaumer Lutz,
Large William A.,
Albert Anthony P.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-238022
Subject(s) - trpc1 , marcks , protein kinase c , phosphorylation , folliculin , microbiology and biotechnology , vascular smooth muscle , phosphatidylinositol , chemistry , transient receptor potential channel , biophysics , biochemistry , biology , endocrinology , receptor , smooth muscle , gene
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)P 2 ] are obligatory for native TRPC1 channel activation in vascular smooth muscle cells (VSMCs) but how PKC and PI(4,5)P 2 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)P 2 . TRPC1 channels and MARCKS form signaling complexes with PI(4,5)P 2 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)P 2 from MARCKS; PI(4,5)P 2 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)P 2 . These novel findings show that MARCKS coordinates native TRPC1 channel activation in VSMCs by acting as a reversible PI(4,5)P 2 buffer, which is regulated by PKC‐mediated TRPC1 phosphorylation. Moreover, our data provide evidence that PI(4,5)P 2 is a gating ligand of TRPC1 channels.—Shi, J., Birnbaumer, L., Large, W. A., and Albert, A. P. Myristoylated alanine‐rich C kinase substrate coordinates native TRPC1 channel activation by phosphatidylinositol 4,5‐bisphosphate and protein kinase C in vascular smooth muscle. FASEB J . 28, 244–255 (2014). www.fasebj.org