Regulation of cAMP by the p75 neurotrophin receptor: insight into drug design of selective phosphodiesterase inhibitors.

Subcellular compartmentalization of PDEs (phosphodiesterases) is a major mechanism for the regulation of cAMP signalling. The identification of the proteins that recruit specific PDE isoforms to subcellular compartments can shed light on the regulation of spatial and temporal cAMP gradients in living cells and provide novel therapeutic targets for inhibiting functions of PDEs. We showed recently that p75(NTR) (p75 neurotrophin receptor) interacts directly with a single PDE isoform, namely PDE4A4/5, via binding to its unique C-terminal region, and targets cAMP degradation to the membrane. The purpose of this review is to present the biological significance of PDE4A compartmentalization by p75(NTR) and discuss the potential of inhibiting the interaction between p75(NTR) and PDE4A for the development of an isoform-specific inhihibitor for PDEs.