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Submitted on February 22, 2005
Accepted on May 4, 2005
Department of Biomedical Sciences, Cornell University, Ithaca NY; Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS
* To whom correspondence should be addressed. E-mail: msr14{at}cornell.edu.
Our previous studies demonstrate that GnRH (GnRH)-induced ERK activation required influx of extracellular Ca2+ in 
T3-1 and rat pituitary cells. In the present studies, we examined the hypothesis that calmodulin (Cam) plays a fundamental role in mediating the effects of Ca2+ on ERK activation. Cam inhibition using W7 was sufficient to block GnRH-induced reporter gene activity for the c-Fos, murine glycoprotein hormone subunit and MKP-2 promoters, all shown to require ERK activation. Inhibition of Cam (using a dominant negative) was sufficient to block GnRH-induced ERK but not JNK activation. The Cam-dependent protein kinase (CamK) II inhibitor KN62 did not recapitulate these findings. GnRH-induced phosphorylation of MEK1 and c-Raf kinase was blocked by Cam inhibition while activity of phospholipase C was unaffected suggesting Ca2+/Cam modulation of the ERK cascade potentially at the level of c-Raf kinase. Enrichment of Cam interacting proteins using a Cam agarose column revealed that c-Raf kinase forms a complex with Cam. Reconstitution studies reveal recombinant c-Raf kinase can associate directly with Cam in a Ca2+-dependent manner and this interaction is reduced in vitro by addition of W7. Cam was localized in lipid rafts consistent with the formation of a Ca2+sensitive signaling platform including the GnRH receptor and c-Raf kinase. These data support the conclusion that Cam may have a critical role as a Ca2+ sensor in specifically linking Ca2+ flux with ERK activation within the GnRH signaling pathway.
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