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PNAS 98 (6): 3168-3173

Copyright © 2001 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Activation of Trp3 by inositol 1,4,5-trisphosphate receptors through displacement of inhibitory calmodulin from a common binding domain

Zongming Zhang*,{dagger}, Jisen Tang*,{dagger}, Svetlana Tikunova{ddagger}, J. David Johnson{ddagger},§, Zhangguo Chen*,{dagger}, Ning Qin, Alexander Dietrich||, Enrico Stefani||, Lutz Birnbaumer||, and Michael Xi Zhu*,{dagger},**

*Neurobiotechnology Center and Departments of {dagger}Neuroscience and {ddagger}Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH 43210; Department of Pharmacology, University of Kentucky, Lexington, KY 40506; and ||Department of Anesthesiology, University of California, Los Angeles, CA 90095

Contributed by Lutz Birnbaumer

Accepted for publication December 29, 2000.

Abstract: 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 IP3Rs.

§ Deceased January 21, 2000.

** To whom reprint requests should be addressed at: Neurobiotechnology Center, Ohio State University, 168 Rightmire Hall, 1060 Carmack Road, Columbus, OH 43210. E-mail: zhu.55{at}osu.edu.

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