¹ACADIA Pharmaceuticals Inc., San Diego, CA 92121, USA

Correspondence: Dr F Piu, ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Boulevard, San Diego, CA 92121, USA. E-mail: fpiu@acadia-pharm.com

Received 22 November 2004; Revised 19 July 2005; Accepted 19 July 2005; Published online 19 September 2005.

Abstract

The activity of retinoid receptors activity can be regulated by various extracellular stimuli. In an effort to understand the molecular basis for this phenomenon, the role of -arrestins was investigated. -Arrestins constitute a class of proteins involved in the internalization of agonist-activated receptors. They have also been linked to MAPK activation suggesting a direct involvement in signaling cascades. Here, we report that -arrestin 2 stimulates the transcriptional activation of the retinoid RAR and RXR receptors. Of all the retinoid receptors, the RAR 2 subtype showed the strongest sensitivity to -arrestin 2 action. Interestingly, this event requires the presence of the MAP kinase ERK2, but not that of JNK or P38. Site-directed mutagenesis showed that Ser 22 and Leu 217 are critical residues of the RAR 2 receptor through which -arrestin 2 effects are mediated. More importantly, we demonstrate that the induction of PC12 growth inhibition by Nerve Growth Factor is indeed dependent upon RAR 2 transcriptional activation in a -arrestin 2- and ERK2-dependent manner.