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J. Cell Biol. 170 (7): 1159-1167

Copyright © 2005 by the Rockefeller University Press.


Cell adhesion molecules regulate Ca2+-mediated steering of growth cones via cyclic AMP and ryanodine receptor type 3

Noriko Ooashi1, Akira Futatsugi2, Fumie Yoshihara1, Katsuhiko Mikoshiba2, , and Hiroyuki Kamiguchi1

1 Laboratory for Neuronal Growth Mechanisms, Brain Science Institute, The Institute of Physical and Chemical Research, Saitama 351-0198, Japan
2 Calcium Oscillation Project, International Cooperative Research Project, Japan Science and Technology Cooperation, Tokyo 108-0071, Japan

Correspondence to Hiroyuki Kamiguchi: kamiguchi{at}

Abstract: Axonal growth cones migrate along the correct paths during development, not only directed by guidance cues but also contacted by local environment via cell adhesion molecules (CAMs). Asymmetric Ca2+ elevations in the growth cone cytosol induce both attractive and repulsive turning in response to the guidance cues (Zheng, J.Q. 2000. Nature. 403:89–93; Henley, J.R., K.H. Huang, D. Wang, and M.M. Poo. 2004. Neuron. 44:909–916). Here, we show that CAMs regulate the activity of ryanodine receptor type 3 (RyR3) via cAMP and protein kinase A in dorsal root ganglion neurons. The activated RyR3 mediates Ca2+-induced Ca2+ release (CICR) into the cytosol, leading to attractive turning of the growth cone. In contrast, the growth cone exhibits repulsion when Ca2+ signals are not accompanied by RyR3-mediated CICR. We also propose that the source of Ca2+ influx, rather than its amplitude or the baseline Ca2+ level, is the primary determinant of the turning direction. In this way, axon-guiding and CAM-derived signals are integrated by RyR3, which serves as a key regulator of growth cone navigation.

Abbreviations used in this paper: AM, acetoxymethyl ester; BAPTA, 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; [Ca2+]c, cytosolic free Ca2+ concentration; CAM, cell adhesion molecule; CCD, charge-coupled device; CG-1, Calcium Green-1; CGRP, calcitonin gene-related peptide; CICR, Ca2+-induced Ca2+ release; DIC, differential interference contrast; DRG, dorsal root ganglion; FLIP, focal laser–induced photolysis; IgSF, immunoglobulin superfamily; MAG, myelin-associated glycoprotein; NP-EGTA, o-nitrophenyl EGTA; PKA, protein kinase A; RyR, ryanodine receptor.

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