PDE4 Is Recruited to Lipid Rafts upon TCR and CD28 CoStimulation

We observed PDE4 activity in lipid rafts upon T-cell activation. In particular, TCR and CD28 co-stimulation resulted in profound raft-associated increase in PDE4 activity (Abrahamsen et al. 2004). This specific increase in PDE4 activity in lipid raft fractions upon TCR and CD28 engagement indicates that temporal changes in PDE4 activity can play a key role in tuning intracellular activation-induced gradients of cAMP in T-cell lipid rafts and thereby increase signal propagation upon co-stimulation. The mechanisms by which PDE4 isoforms are recruited to specific locations upon T-cell activation are now being unraveled (Abrahamsen et al. 2004; Arp et al. 2003). We have demonstrated that PDE4A4, 4B2 and 4D1/2 are recruited to lipid rafts upon TCR and CD28 co-stimulation in human peripheral T cells (Abrahamsen et al. 2004). Members of the PDE4 family have previously been described to associate with the scaffolding protein P-arrestin, and P-arrestin has been shown to be responsible for bringing PDE4 to the plasma membrane of HEK293 cells and to the activated G-protein-coupled receptor (GPCR) where cAMP production is taking place (Perry et al. 2002). Intriguingly, we found that both TCR and CD28 co-stimulation and CD28 stimulation alone caused a clear recruitment of P-arrestin to T-cell lipid raft fractions concurrently with PDE4. In addition, immunoprecipitation from both unstimulated and co-stimulated cells revealed that P-arrestin and PDE4 pre-exist in a complex prior to stimulation, indicating that they are recruited to rafts together (Abrahamsen et al. 2004).

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