Arrestin Interactions During LH Receptor Desensitization

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The luteinizing hormone (LH) receptor is a seven transmembrane spanning receptor coupled to G proteins, most typically Gs, which activates adenylyl cyclase to transduce a second messenger signal. Signal transduction by the LH receptor is tempered by a molecular mechanism known as desensitization. Although desensitization of the LH receptor may involve attenuation of receptor function, G protein function, or the downstream effector, the inability of receptors to activate their respective G-protein due to associations with arrestin molecules appears to be a key event leading to receptor desensitization. Recent studies from our laboratory have elucidated various proteins necessary for beta-arrestin interaction with the LH receptor and a potential new role for beta-arrestins in signal transduction. I hypothesize that within an intact cell ARF nucleotide-binding site opener (ARNO) activates ADP ribosylation factor 6 (ARF6) which leads to the release of beta-arrestin-1 from its membrane docking site. Once released, beta-arrestin-1 binds to the activated LH receptor and inhibits further signaling through heterotrimeric G proteins. The arrestin-receptor complex then recruits Src and/or Grb-2 to initiate a different signaling pathway, the Akt signaling pathway. To test this hypothesis, I propose three specific aims to clarify the molecular mechanisms involved in the release of and signal transduction via beta- arrestin following activation of the LH receptor.