Molecular determinants for cardiovascular TRPC6 channel regulation by Ca2+/calmodulin‐dependent kinase II

•  Ca2+/calmodulin (CaM)‐dependent kinase II (CaMKII) plays pivotal roles in diverse Ca2+‐mediated cellular functions including the physiology/pathophysiology of the cardiovascular system, through modulation of a variety of Ca2+‐permeable channels such as a non‐voltage‐gated Ca2+ channel TRPC6. •  In this study, we investigated the molecular mechanism underlying its positive regulation by CaMKII with chimera, deletion and site‐directed mutagenesis approaches. •  The results indicate that two spatially separated sites of TRPC6 channel, i.e. a distal part of the C‐terminal inositol‐1,4,5‐trisphosphate receptor/CaM binding domain and Thr487 located on the putative first intracellular loop, are crucial for the CaMKII‐mediated regulation of TRPC6 channels. •  This mechanism may serve as an effective positive feedback regulation of Ca2+ influx through TRPC6 channels, in concert with intracellular and transmembrane Ca2+ mobilization upon phospholipase C‐coupled receptor stimulation by neurohormonal factors, thereby fine‐tuning the cardiovascular functions. •  Disruption of these could lead to pathological states such as cardiac hypertrophy and arrhythmia, hypertension and atherosclerosis.

[1]  Mark E. Anderson,et al.  The multifunctional Ca2+/calmodulin-dependent kinase II regulates vascular smooth muscle migration through matrix metalloproteinase 9. , 2012, American journal of physiology. Heart and circulatory physiology.

[2]  H. Singer.  Ca2+/calmodulin‐dependent protein kinase II function in vascular remodelling , 2012, The Journal of physiology.

[3]  M. Nishida,et al.  Cilostazol Suppresses Angiotensin II–Induced Vasoconstriction via Protein Kinase A–Mediated Phosphorylation of the Transient Receptor Potential Canonical 6 Channel , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[4]  S. Shyue,et al.  Molecular mechanisms of activation of endothelial nitric oxide synthase mediated by transient receptor potential vanilloid type 1. , 2011, Cardiovascular research.

[5]  M. Mori,et al.  Quantitative measurement of Ca(2+)-dependent calmodulin-target binding by Fura-2 and CFP and YFP FRET imaging in living cells. , 2011, Biochemistry.

[6]  J. Mcgeown,et al.  VEGF-induced retinal angiogenic signaling is critically dependent on Ca²⁺ signaling by Ca²⁺/calmodulin-dependent protein kinase II. , 2011, Investigative ophthalmology & visual science.

[7]  Ching-On Wong,et al.  cAMP Activates TRPC6 Channels via the Phosphatidylinositol 3-Kinase (PI3K)-Protein Kinase B (PKB)-Mitogen-activated Protein Kinase Kinase (MEK)-ERK1/2 Signaling Pathway* , 2011, The Journal of Biological Chemistry.

[8]  Mark E. Anderson,et al.  The Multifunctional Ca2+/Calmodulin-dependent Kinase II δ (CaMKIIδ) Controls Neointima Formation after Carotid Ligation and Vascular Smooth Muscle Cell Proliferation through Cell Cycle Regulation by p21* , 2010, The Journal of Biological Chemistry.

[9]  Thomas J Hund,et al.  A β(IV)-spectrin/CaMKII signaling complex is essential for membrane excitability in mice. , 2010, The Journal of clinical investigation.

[10]  F. Hofmann,et al.  Facilitation of murine cardiac L-type Cav1.2 channel is modulated by Calmodulin kinase II–dependent phosphorylation of S1512 and S1570 , 2010, Proceedings of the National Academy of Sciences.

[11]  G. Tomaselli,et al.  Na+ channel regulation by Ca2+/calmodulin and Ca2+/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes. , 2010, Cardiovascular research.

[12]  R. Colbran,et al.  CaMKII associates with CaV1.2 L‐type calcium channels via selected β subunits to enhance regulatory phosphorylation , 2010, Journal of neurochemistry.

[13]  D. Bers,et al.  Calcium/Calmodulin-dependent Kinase II Regulation of Cardiac Ion Channels , 2009, Journal of cardiovascular pharmacology.

[14]  U. Schotten,et al.  Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. , 2009, The Journal of clinical investigation.

[15]  Y. Mori,et al.  Synergistic Activation of Vascular TRPC6 Channel by Receptor and Mechanical Stimulation via Phospholipase C/Diacylglycerol and Phospholipase A2/&ohgr;-Hydroxylase/ 20-HETE Pathways , 2009, Circulation research.

[16]  M. Kameyama,et al.  CaMKII phosphorylates a threonine residue in the C-terminal tail of Cav1.2 Ca2+ channel and modulates the interaction of the channel with calmodulin , 2009, The Journal of Physiological Sciences.

[17]  Y. Mori,et al.  Nitric oxide–cGMP–protein kinase G pathway negatively regulates vascular transient receptor potential channel TRPC6 , 2008, The Journal of physiology.

[18]  M. Anderson,et al.  The role of calmodulin kinase II in myocardial physiology and disease. , 2008, Physiology.

[19]  T. Walther,et al.  Role of Ca2+/calmodulin‐dependent protein kinase II in development of vascular dysfunction in diabetic rats with hypertension , 2008, Cell biochemistry and function.

[20]  G. Pitt.  Calmodulin and CaMKII as molecular switches for cardiac ion channels. , 2007, Cardiovascular research.

[21]  P. Barrett,et al.  Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+/calmodulin-dependent protein kinase II. , 2006, The Journal of clinical investigation.

[22]  H. Kwan,et al.  Regulation of TRP Channels by Phosphorylation , 2006, Neurosignals.

[23]  D. Bers,et al.  Ca2+/Calmodulin–Dependent Protein Kinase Modulates Cardiac Ryanodine Receptor Phosphorylation and Sarcoplasmic Reticulum Ca2+ Leak in Heart Failure , 2005, Circulation research.

[24]  J. Hell,et al.  Activity-driven postsynaptic translocation of CaMKII. , 2005, Trends in pharmacological sciences.

[25]  James Kim,et al.  CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation , 2005, The Journal of cell biology.

[26]  D. Bers,et al.  Cardiac Type 2 Inositol 1,4,5-Trisphosphate Receptor , 2005, Journal of Biological Chemistry.

[27]  Y. Mori,et al.  Multiple regulation by calcium of murine homologues of transient receptor potential proteins TRPC6 and TRPC7 expressed in HEK293 cells , 2004, The Journal of physiology.

[28]  H. Schulman.  Activity-Dependent Regulation of Calcium/Calmodulin-Dependent Protein Kinase II Localization , 2004, The Journal of Neuroscience.

[29]  J. Brown,et al.  Role of Ca2+/calmodulin-dependent protein kinase II in cardiac hypertrophy and heart failure. , 2004, Cardiovascular research.

[30]  I. Ambudkar,et al.  Biogenesis and Topology of the Transient Receptor Potential Ca2+ Channel TRPC1* , 2004, Journal of Biological Chemistry.

[31]  S. Hwang,et al.  Phosphorylation of Vanilloid Receptor 1 by Ca2+/Calmodulin-dependent Kinase II Regulates Its Vanilloid Binding* , 2004, Journal of Biological Chemistry.

[32]  T. Gudermann,et al.  N-Linked Protein Glycosylation Is a Major Determinant for Basal TRPC3 and TRPC6 Channel Activity* , 2003, Journal of Biological Chemistry.

[33]  P. Barrett,et al.  A Mechanism for the Direct Regulation of T-Type Calcium Channels by Ca2+/Calmodulin-Dependent Kinase II , 2003, The Journal of Neuroscience.

[34]  T. Soderling,et al.  Structure and regulation of calcium/calmodulin-dependent protein kinases. , 2001, Chemical reviews.

[35]  M. Zhu,et al.  Identification of Common Binding Sites for Calmodulin and Inositol 1,4,5-Trisphosphate Receptors on the Carboxyl Termini of Trp Channels* , 2001, The Journal of Biological Chemistry.

[36]  Paul De Koninck,et al.  Interaction with the NMDA receptor locks CaMKII in an active conformation , 2001, Nature.

[37]  T. Soderling,et al.  A structural basis for substrate specificities of protein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA, phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1 , 1996, Molecular and cellular biology.

[38]  T. Soderling.  Structure and regulation of calcium/calmodulin-dependent protein kinases II and IV. , 1996, Biochimica et biophysica acta.

[39]  R. Hurst,et al.  trp, a Novel Mammalian Gene Family Essential for Agonist-Activated Capacitative Ca2+ Entry , 1996, Cell.

[40]  A. Ishida,et al.  A novel highly specific and potent inhibitor of calmodulin-dependent protein kinase II. , 1995, Biochemical and biophysical research communications.

[41]  Mark E. Anderson,et al.  The multifunctional Ca 2 / calmodulin-dependent kinase II regulates vascular smooth muscle migration through matrix metalloproteinase 9 , 2012 .

[42]  T. Nishiya,et al.  Function and regulation of endothelin type A receptor-operated transient receptor potential canonical channels. , 2011, Journal of pharmacological sciences.

[43]  I. So,et al.  Involvement of calmodulin kinase II in the action of sulphur mustard on the contraction of vascular smooth muscle. , 2011, Basic & clinical pharmacology & toxicology.

[44]  E. Olson,et al.  The Multifunctional Ca 2 / Calmodulin-dependent Kinase II ( CaMKII ) Controls Neointima Formation after Carotid Ligation and Vascular Smooth Muscle Cell Proliferation through Cell Cycle Regulation by p 21 * , 2011 .

[45]  Andy Hudmon,et al.  Neuronal CA2+/calmodulin-dependent protein kinase II: the role of structure and autoregulation in cellular function. , 2002, Annual review of biochemistry.