Sci. STKE, 4 October 2005
NEUROSCIENCE Converting Repulsion to Attraction with CICR
Growth cones guide neurites to their targets by monitoring chemoattractive and chemorepellant cues. Many cues elicit localized increases in cytosolic free calcium concentration ([Ca2+]c), but, curiously, both attractive and repulsive diffusible cues can increase [Ca2+]c on the side of the growth cone facing the source of the gradient so that the growth cone turns toward (attraction) or away from (repulsion) the side with greater [Ca2+]c. Ooashi et al. used focal laser-induced photolysis (FLIP) of caged Ca2+ to transiently increase [Ca2+]c in the growth cones of dorsal root ganglion (DRG) neurons grown on different substrata. Neurons grown on L1 or N-cadherin turned toward, whereas neurons grown on laminin turned away from, the side on which [Ca2+]c was greater. Neurons grown on L1 and N-cadherin had more adenosine 3',5'-monophosphate (cAMP) and showed increased cAMP binding to the regulatory subunits of cAMP-dependent protein kinase (PKA) than did neurons grown on laminin. Inhibition of cAMP signaling converted Ca2+-mediated attraction to repulsion, whereas pharmacological activation of PKA converted Ca2+-mediated repulsion to attraction. PKA phosphorylates ryanodine receptors (RyRs), facilitating calcium-induced calcium release (CICR), and pharmacological analysis combined with calcium imaging in conjunction with FLIP showed PKA-dependent activation of RyR-mediated CICR in growth cones on L1 or N-cadherin. Analysis of calcium signals and of the turning behavior of DRG neurons from mice lacking the type 3 RyR isoform (RyR3) implicated RyR3 in PKA-dependent CICR and attractive turning. Experiments with calcium buffers or with different amounts of the Ca2+-caging compound indicated that the source of the cytosolic Ca2+ signal--rather than its amplitude--determined turning behavior. Thus, the authors conclude that a Ca2+ signal that triggers CICR stimulates attractive turning, whereas a Ca2+ signal without CICR elicits repulsion.
N. Ooashi, A. Futatsugi, F. Yoshihara, K. Mikoshiba, H. Kamiguchi, Cell adhesion molecules regulate Ca2+-mediated steering of growth cones via cyclic AMP and ryanodine receptor type 3. J. Cell Biol. 170, 1159-1167 (2005). [Abstract] [Full Text]
Citation: Converting Repulsion to Attraction with CICR. Sci. STKE 2005, tw347 (2005).
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