Activation of Trp3 by Inositol 1,4,5-Trisphosphate Receptors through Displacement of Inhibitory Calmodulin from a Common Binding Domain

Mammalian homologues of Drosophila Trp form plasma membrane channels that mediate Ca2+ influx in response to activation of phospholipase C and internal Ca2+ store depletion. Previous studies showed that human Trp3 is activated by inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) and identified in...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2001-03, Vol.98 (6), p.3168-3173
Hauptverfasser: Zhang, Zongming, Tang, Jisen, Tikunova, Svetlana, Johnson, J. David, Chen, Zhangguo, Qin, Ning, Dietrich, Alexander, Stefani, Enrico, Birnbaumer, Lutz, Zhu, Michael Xi
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Sprache:eng
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Zusammenfassung:Mammalian homologues of Drosophila Trp form plasma membrane channels that mediate Ca2+ influx in response to activation of phospholipase C and internal Ca2+ store depletion. Previous studies showed that human Trp3 is activated by inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) and identified interacting domains, one on Trp and two on IP3R. We now find that Trp3 binds Ca2+-calmodulin (Ca2+/CaM) at a site that overlaps with the IP3R binding domain. Using patch-clamp recordings from inside-out patches, we further show that Trp3 has a high intrinsic activity that is suppressed by Ca2+/CaM under resting conditions, and that Trp3 is activated by the following: a Trp-binding peptide from IP3R that displaces CaM from Trp3, a myosin light chain kinase Ca2+/CaM binding peptide that prevents CaM from binding to Trp3, and calmidazolium, an inactivator of Ca2+/CaM. We conclude that inhibition of the inhibitory action of CaM is a key step of Trp3 channel activation by IP3RsRs.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.051632698