Damage to the CNS axons in stroke, neurodegenerative diseases such as multiple sclerosis and Alzheimer’s disease as well as in traumatic injury is devastating due to the limited regenerative capacity of the adult CNS. Elevation of cAMP in neurons, either by cAMP analogs or by inhibition of type four phosphodiesterases (PDEs), the enzymes responsible for the breakdown of cAMP, overcomes inhibition of axonal regeneration (1). However, the lack of selectivity among PDE4 inhibitors, such as rolipram, has limited their clinical applications (2). Failure to develop specific PDE4 inhibitors has been primarily due to selecting the catalytic domain as a therapeutic target, which is highly homologous between the different PDE4 isoforms (2). Here we show that the p75 neurotrophin receptor (p75NTR), a TNF receptor superfamily member that is upregulated upon nervous system injury (3), downregulates cAMP in neuronal cells by direct interaction with the unique C-terminus domain of phosphodiesterase 4A5 (PDE4A5). We initially observed that overexpression of p75NTR in NIH3T3 fibroblasts induces a reduction in cAMP that is rescued by the PDE4 specific inhibitor rolipram. To examine whether p75NTR regulates cAMP in neuronal cells, we isolated cerebellar granular neurons (CGNs) from p75NTR -/- and wild-type animals and showed that loss of p75NTR in neurons results in increase of cAMP. Immunostaining of postnatal mouse cerebellum with specific antibodies against different PDE4s, showed specific expression of PDE4A in CGNs. To examine the mechanism linking PDE4-mediated p75NTR downregulation of cAMP, we investigated the hypothesis whether p75NTR could directly recruit members of the PDE4 family to the membrane, a mechanism previously shown to induce cAMP degradation by adrenergic receptors (4). Co-immunoprecipitation experiments using isoform-specific antibodies showed that p75NTR specifically recruits the PDE4A5 isoform to the membrane. A membrane-targeted fluorescent reporter of PKA activity that generates a change in fluorescence resonance energy transfer (FRET) when it is phosphorylated at the membrane of living cells (5), showed reduced PKA activity at the membrane upon expression of p75NTR. Deletions of the intracellular domain of p75NTR indicated that the juxtamembrane amino acid sequence 275R-342L is necessary for the interaction with PDE4A5. To determine whether the p75NTR – PDE4A5 interaction was direct, we screened a PDE4A4/5 peptide library with the intracellular domain of p75NTR. We identified the LR1 and C-terminal unique regions of PDE4A4/5 as the interacting motifs directly interacting with p75NTR. Our results identify p75NTR as the first membrane receptor that can recruit PDE4A4/5 to the membrane and thus regulate intracellular levels of cAMP. The biological significance of targeting the p75NTR / PDE4A5 interaction in neuronal functions will be discussed.