Sensing of Lysophospholipids by TRPC5 Calcium Channel*

TRPC calcium channels are emerging as a ubiquitous feature of vertebrate cells, but understanding of them is hampered by limited knowledge of the mechanisms of activation and identity of endogenous regulators. We have revealed that one of the TRPC channels, TRPC5, is strongly activated by common endogenous lysophospholipids including lysophosphatidylcholine (LPC) but, by contrast, not arachidonic acid. Although TRPC5 was stimulated by agonists at G-protein-coupled receptors, TRPC5 activation by LPC occurred downstream and independently of G-protein signaling. The effect was not due to the generation of reactive oxygen species or because of a detergent effect of LPC. LPC activated TRPC5 when applied to excised membrane patches and thus has a relatively direct action on the channel structure, either because of a phospholipid binding site on the channel or because of sensitivity of the channel to perturbation of the bilayer by certain lipids. Activation showed dependence on side-chain length and the chemical head-group. The data revealed a previously unrecognized lysophospholipid-sensing capability of TRPC5 that confers the property of a lipid ionotropic receptor.

[1]  M. Freichel,et al.  A novel capacitative calcium entry channel expressed in excitable cells , 1998, The EMBO journal.

[2]  T. Gudermann,et al.  Receptor-mediated Regulation of the Nonselective Cation Channels TRPC4 and TRPC5* , 2000, The Journal of Biological Chemistry.

[3]  M. Schaefer,et al.  TRPC4 and TRPC5: receptor-operated Ca2+-permeable nonselective cation channels. , 2003, Cell calcium.

[4]  J. Axelrod,et al.  A transfected m5 muscarinic acetylcholine receptor stimulates phospholipase A2 by inducing both calcium influx and activation of protein kinase C. , 1990, The Journal of pharmacology and experimental therapeutics.

[5]  H. Suh,et al.  Therapeutic effects of lysophosphatidylcholine in experimental sepsis , 2004, Nature Medicine.

[6]  J. Putney The enigmatic TRPCs: multifunctional cation channels. , 2004, Trends in cell biology.

[7]  Vassilios J. Bezzerides,et al.  Rapid vesicular translocation and insertion of TRP channels , 2004, Nature Cell Biology.

[8]  L. Vaca,et al.  Calmodulin and Calcium Interplay in the Modulation of TRPC5 Channel Activity , 2005, Journal of Biological Chemistry.

[9]  A. Perraud,et al.  Critical Intracellular Ca2+ Dependence of Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel Activation* , 2003, The Journal of Biological Chemistry.

[10]  J. Chun,et al.  Lysophospholipid receptors: signaling and biology. , 2004, Annual review of biochemistry.

[11]  M. Freichel,et al.  Functional role of TRPC proteins in native systems: implications from knockout and knock‐down studies , 2005, The Journal of physiology.

[12]  Bernd Nilius,et al.  TRP channels: a TR(I)P through a world of multifunctional cation channels , 2005, Pflügers Archiv.

[13]  G. Mills,et al.  Elevated levels and altered fatty acid composition of plasma lysophosphatidlycholine(lysoPC) in ovarian cancer patients , 1997, International journal of cancer.

[14]  S. Kawashima,et al.  Lysophosphatidylcholine enhances superoxide anions production via endothelial NADH/NADPH oxidase. , 2000, Journal of atherosclerosis and thrombosis.

[15]  D. Clapham,et al.  TRPC1 and TRPC5 Form a Novel Cation Channel in Mammalian Brain , 2001, Neuron.

[16]  Stanley L. Hazen,et al.  Identification of &agr;-Chloro Fatty Aldehydes and Unsaturated Lysophosphatidylcholine Molecular Species in Human Atherosclerotic Lesions , 2003 .

[17]  M. Nowycky,et al.  A Cytosolic Residue Mediates Mg2+ Block and Regulates Inward Current Amplitude of a Transient Receptor Potential Channel , 2005, The Journal of Neuroscience.

[18]  N. Shimizu,et al.  LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. , 2002, Molecular cell.

[19]  B. Nilius,et al.  Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels , 2003, Nature.

[20]  Christian R. Halaszovich,et al.  The TRP family of cation channels: probing and advancing the concepts on receptor-activated calcium entry , 2002, Progress in Neurobiology.

[21]  P. McIntyre,et al.  A TRP Channel that Senses Cold Stimuli and Menthol , 2002, Cell.

[22]  G. Babnigg,et al.  Functional significance of human trp1 and trp3 in store-operated Ca(2+) entry in HEK-293 cells. , 2000, American journal of physiology. Cell physiology.

[23]  D. Julius,et al.  The vanilloid receptor: a molecular gateway to the pain pathway. , 2001, Annual review of neuroscience.

[24]  R. Gross,et al.  Depletion of Intracellular Calcium Stores Activates Smooth Muscle Cell Calcium-independent Phospholipase A2 , 1997, The Journal of Biological Chemistry.

[25]  K. Muraki,et al.  Non‐selective cationic channels of smooth muscle and the mammalian homologues of Drosophila TRP , 2004, The Journal of physiology.

[26]  T. Smani,et al.  A novel mechanism for the store-operated calcium influx pathway , 2004, Nature Cell Biology.

[27]  D. McKemy,et al.  Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1 , 2004, Nature.