Modulation of synaptic signal transduction by cross-talk between Ca2+- and Rho-dependent signaling.

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Signaling from synapse to nucleus triggers activation of nuclear CaMKIV in a synpatic activity-dependent manner. We previously showed that Ca2+-influx channels that mediate this response are localized to the synapse. However the molecular and ctoskeletal mechanisms by which this is achieved remains unsolved. Here, we considered the possibility that molecules involved in Rho small GTPase signaling might contribute to such a process. By investigating a potential physical link between components of synaptic activity-dependent Ca2+-mobilization mechanisms and components of Rho-mediated signaling, we discovered :1) the presence of a novel synaptic protein complex consisting of a Rho-effector, Citron-N, and PSD- 95/NMDA-receptor subunits ;2) an association between Cupidin/Homer2a/Vesl2 and Rho-actin cytoskeleton system. These findings represent the first molecular indication that Rho signaling may truly participate in organizing a synaptic Ca2+-mobilization complex, either at the level of NMDA receptors or the intracellular Ca2+ stores. Furthermore, during the course of these studies, we established that :3) Rho/ROCK signaling functions as a gate critical for the negative regulation of axonal outgrowth during cerebellar granule cell development ;4) a novel proteolytic cleavage of CaMKIV may represent a novel mechanism to control the amount of activation of the CaMKIV/CREB pathway ; such regulatory process may be implicated in the maintainance of survival in cerebellar granule cells in culture.