To Kenneth C W, Church John, O'Connor Timothy P
Department of Cellular and Physiological Sciences and Graduate Program in Neuroscience, University of British Columbia, 2350 Health Sciences Mall, Vancouver, B.C., Canada.
Mol Cell Neurosci. 2007 Dec;36(4):425-34. doi: 10.1016/j.mcn.2007.08.001. Epub 2007 Aug 9.
Calcium plays a key role during growth cone collapse. Recently, it has been proposed that low- and high-amplitude rises in Ca(2+) result in the activation of the neurite outgrowth inhibiting proteins calcineurin and calpain, respectively. However, it remains unknown if and how these mechanisms are modulated by specific guidance cues. Here we report that the inhibitory cue Semaphorin 5B induces growth cone collapse by promoting the influx of extracellular Ca(2+). The resulting rise in Ca(2+) is characterized by a low-amplitude increase followed by a marked secondary rise, suggesting the potential involvement of both calcineurin and calpain. In support of this, inhibition of either effector attenuated Sema5B-induced collapse, a result that was augmented by the simultaneous inhibition of both targets. Furthermore, we provide evidence that Sema5B induces calpain-mediated cleavage of calcineurin. We thus show for the first time that ligand-induced growth cone collapse can activate both calcineurin- and calpain-mediated pathways concurrently.
钙在生长锥塌陷过程中起关键作用。最近，有人提出细胞内钙离子浓度（[Ca(2+)]i）的低幅度和高幅度升高分别导致神经突生长抑制蛋白钙调神经磷酸酶和钙蛋白酶的激活。然而，这些机制是否以及如何受到特定导向线索的调节仍不清楚。在此我们报告，抑制性线索信号素5B（Semaphorin 5B）通过促进细胞外钙离子内流诱导生长锥塌陷。由此导致的[Ca(2+)]i升高的特征是先有低幅度增加，随后有明显的二次升高，这表明钙调神经磷酸酶和钙蛋白酶都可能参与其中。支持这一点的是，对任一效应器的抑制都会减弱信号素5B诱导的塌陷，同时抑制两个靶点会增强这一结果。此外，我们提供证据表明信号素5B诱导钙蛋白酶介导的钙调神经磷酸酶的切割。因此，我们首次表明配体诱导的生长锥塌陷可同时激活钙调神经磷酸酶和钙蛋白酶介导的途径。
