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PNAS 109 (20): 7888-7892

Copyright © 2012 by the National Academy of Sciences.


Calpain cleaves and activates the TRPC5 channel to participate in semaphorin 3A-induced neuronal growth cone collapse

J. Stefan Kaczmareka,1, Antonio Ricciob,c,1, and David E. Claphamb,c,2

aProgram in Neuroscience, Division of Medical Sciences, Harvard University, Boston, MA 02115; bHoward Hughes Medical Institute, Department of Cardiology, Manton Center for Orphan Disease, Children’s Hospital Boston, MA 02115; and cDepartment of Neurobiology, Harvard Medical School, Boston, MA 02115

Contributed by David E. Clapham, April 6, 2012 (sent for review March 17, 2012)

Abstract: The nonselective cation channel transient receptor potential canonical (TRPC)5 is found predominantly in the brain and has been proposed to regulate neuronal processes and growth cones. Here, we demonstrate that semaphorin 3A-mediated growth cone collapse is reduced in hippocampal neurons from TRPC5 null mice. This reduction is reproduced by inhibition of the calcium-sensitive protease calpain in wild-type neurons but not in TRPC5–/– neurons. We show that calpain-1 and calpain-2 cleave and functionally activate TRPC5. Mutation of a critical threonine at position 857 inhibits calpain-2 cleavage of the channel. Finally, we show that the truncated TRPC5 predicted to result from calpain cleavage is functionally active. These results indicate that semaphorin 3A initiates growth cone collapse via activation of calpain that in turn potentiates TRPC5 activity. Thus, TRPC5 acts downstream of semaphorin signaling to cause changes in neuronal growth cone morphology and nervous system development.

Key Words: hippocampus • TRP channel • calcium signaling • neuronal development

Author contributions: J.S.K. and D.E.C. designed research; J.S.K. and A.R. performed research; J.S.K. and A.R. contributed new reagents/analytic tools; J.S.K., A.R., and D.E.C. analyzed data; and J.S.K. and D.E.C. wrote the paper.

1J.S.K. and A.R. contributed equally to this work.

The authors declare no conflict of interest.

2To whom correspondence should be addressed. E-mail: dclapham{at}

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