Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2013 Feb 22;2888:5278-90. doi: 10.1074/jbc.M112.409482.
Show Gene links
Show Anatomy links
Interplay between calmodulin and phosphatidylinositol 4,5-bisphosphate in Ca2+-induced inactivation of transient receptor potential vanilloid 6 channels.
Cao C, Zakharian E, Borbiro I, Rohacs T.
???displayArticle.abstract???
The epithelial Ca(2+) channel transient receptor potential vanilloid 6 (TRPV6) undergoes Ca(2+)-induced inactivation that protects the cell from toxic Ca(2+) overload and may also limit intestinal Ca(2+) transport. To dissect the roles of individual signaling pathways in this phenomenon, we studied the effects of Ca(2+), calmodulin (CaM), and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) in excised inside-out patches. The activity of TRPV6 strictly depended on the presence of PI(4,5)P(2), and Ca(2+)-CaM inhibited the channel at physiologically relevant concentrations. Ca(2+) alone also inhibited TRPV6 at high concentrations (IC(50) = ∼20 μM). A double mutation in the distal C-terminal CaM-binding site of TRPV6 (W695A/R699E) essentially eliminated inhibition by CaM in excised patches. In whole cell patch clamp experiments, this mutation reduced but did not eliminate Ca(2+)-induced inactivation. Providing excess PI(4,5)P(2) reduced the inhibition by CaM in excised patches and in planar lipid bilayers, but PI(4,5)P(2) did not inhibit binding of CaM to the C terminus of the channel. Overall, our data show a complex interplay between CaM and PI(4,5)P(2) and show that Ca(2+), CaM, and the depletion of PI(4,5)P(2) all contribute to inactivation of TRPV6.
Bers,
A practical guide to the preparation of Ca(2+) buffers.
2010, Pubmed
Bers,
A practical guide to the preparation of Ca(2+) buffers.
2010,
Pubmed Colquhoun,
Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors.
1998,
Pubmed Crivici,
Molecular and structural basis of target recognition by calmodulin.
1995,
Pubmed Csanády,
Four Ca2+ ions activate TRPM2 channels by binding in deep crevices near the pore but intracellularly of the gate.
2009,
Pubmed
,
Xenbase Cui,
CaT1 contributes to the stores-operated calcium current in Jurkat T-lymphocytes.
2002,
Pubmed de Groot,
Molecular mechanisms of calmodulin action on TRPV5 and modulation by parathyroid hormone.
2011,
Pubmed Derler,
Dynamic but not constitutive association of calmodulin with rat TRPV6 channels enables fine tuning of Ca2+-dependent inactivation.
2006,
Pubmed Hansen,
Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.
2011,
Pubmed Hilgemann,
The complex and intriguing lives of PIP2 with ion channels and transporters.
2001,
Pubmed Hoenderop,
Calcium absorption across epithelia.
2005,
Pubmed Holakovska,
Characterization of calmodulin binding domains in TRPV2 and TRPV5 C-tails.
2011,
Pubmed Kovalevskaya,
The TRPV5/6 calcium channels contain multiple calmodulin binding sites with differential binding properties.
2012,
Pubmed
,
Xenbase Kwon,
Integration of phosphoinositide- and calmodulin-mediated regulation of TRPC6.
2007,
Pubmed Lambers,
Regulation of the mouse epithelial Ca2(+) channel TRPV6 by the Ca(2+)-sensor calmodulin.
2004,
Pubmed
,
Xenbase Lee,
PIP2 activates TRPV5 and releases its inhibition by intracellular Mg2+.
2005,
Pubmed Logothetis,
Dynamic changes in phosphoinositide levels control ion channel activity.
2007,
Pubmed Lopes,
Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies.
2002,
Pubmed
,
Xenbase Lukacs,
Dual regulation of TRPV1 by phosphoinositides.
2007,
Pubmed
,
Xenbase McLaughlin,
Plasma membrane phosphoinositide organization by protein electrostatics.
2005,
Pubmed Niemeyer,
Competitive regulation of CaT-like-mediated Ca2+ entry by protein kinase C and calmodulin.
2001,
Pubmed Nilius,
Transient receptor potential channels meet phosphoinositides.
2008,
Pubmed Nilius,
Fast and slow inactivation kinetics of the Ca2+ channels ECaC1 and ECaC2 (TRPV5 and TRPV6). Role of the intracellular loop located between transmembrane segments 2 and 3.
2002,
Pubmed Parekh,
Ca2+ microdomains near plasma membrane Ca2+ channels: impact on cell function.
2008,
Pubmed Park,
Altered biochemical properties of transient receptor potential vanilloid 6 calcium channel by peptide tags.
2009,
Pubmed Persechini,
The relationship between the free concentrations of Ca2+ and Ca2+-calmodulin in intact cells.
1999,
Pubmed Rohacs,
Phosphoinositide regulation of non-canonical transient receptor potential channels.
2009,
Pubmed Rohacs,
Regulation of transient receptor potential (TRP) channels by phosphoinositides.
2007,
Pubmed Rohács,
PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain.
2005,
Pubmed Rohács,
Assaying phosphatidylinositol bisphosphate regulation of potassium channels.
2002,
Pubmed
,
Xenbase Rohács,
Specificity of activation by phosphoinositides determines lipid regulation of Kir channels.
2003,
Pubmed
,
Xenbase Rosenhouse-Dantsker,
Molecular characteristics of phosphoinositide binding.
2007,
Pubmed Saimi,
Calmodulin as an ion channel subunit.
2002,
Pubmed Suh,
PIP2 is a necessary cofactor for ion channel function: how and why?
2008,
Pubmed Thyagarajan,
Phospholipase C-mediated regulation of transient receptor potential vanilloid 6 channels: implications in active intestinal Ca2+ transport.
2009,
Pubmed Thyagarajan,
Hydrolysis of phosphatidylinositol 4,5-bisphosphate mediates calcium-induced inactivation of TRPV6 channels.
2008,
Pubmed Weissgerber,
Male fertility depends on Ca²+ absorption by TRPV6 in epididymal epithelia.
2011,
Pubmed Whorton,
Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium.
2011,
Pubmed
,
Xenbase Zakharian,
Intracellular ATP supports TRPV6 activity via lipid kinases and the generation of PtdIns(4,5) P₂.
2011,
Pubmed
,
Xenbase Zhu,
Multiple roles of calmodulin and other Ca(2+)-binding proteins in the functional regulation of TRP channels.
2005,
Pubmed
