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Published online 25 July 2005. doi:10.1083/jcb.200409157
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 3, 429-441
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Article

 Reversible intracellular translocation of KRas but not HRas in hippocampal neurons regulated by Ca2+/calmodulin

Marc Fivaz and Tobias Meyer

Department of Molecular Pharmacology, Stanford University School of Medecine, Stanford, CA 94305

Correspondence to Marc Fivaz: mfivaz{at}stanford.edu; or Tobias Meyer: Tobias1{at}stanford.edu

The Ras/MAPK pathway regulates synaptic plasticity and cell survival in neurons of the central nervous system. Here, we show that KRas, but not HRas, acutely translocates from the plasma membrane (PM) to the Golgi complex and early/recycling endosomes in response to neuronal activity. Translocation is reversible and mediated by the polybasic-prenyl membrane targeting motif of KRas. We provide evidence that KRas translocation occurs through sequestration of the polybasic-prenyl motif by Ca2+/calmodulin (Ca2+/CaM) and subsequent release of KRas from the PM, in a process reminiscent of GDP dissociation inhibitor–mediated membrane recycling of Rab and Rho GTPases. KRas translocation was accompanied by partial intracellular redistribution of its activity. We conclude that the polybasic-prenyl motif acts as a Ca2+/CaM-regulated molecular switch that controls PM concentration of KRas and redistributes its activity to internal sites. Our data thus define a novel signaling mechanism that differentially regulates KRas and HRas localization and activity in neurons.

Abbreviations used in this paper: DIV, days in vitro; GDI, GDP dissociation inhibitor; NMDA-R, N-methyl-D-aspartate receptor; PM, plasma membrane; PN, perinuclear; PNS, postnuclear supernatant; RBD, Ras-binding domain of Raf-1.


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