PDE4D Enzyme

Pathway Information

PDE4D is a phosphodiesterase subunit heavily localized to layer III dlPFC [2].

It is an Enzyme that when modulated significantly impacts high-level cognition. It is a very attractive target for developing nootropics / anti-tauopathy candidates, and is worthy of investigation.

PDE4D could be described as similar to mGluR3 in function and expression, however there are some notable differences. For one, PDE4D is not metabotropic like mGluRs. Also PDE4D is largely regulated through Phosphorylation, while mGluR3 is regulated largely through NAAG and expression directly.

One study found that genetic ablation of the long PDE4D isoforms PDE4D3, -D5, -D7, and -D9 increased average neurite length both in absence and in presence of the neurotoxic Aβ1-42 concentration. Genetic knockdown of the other long isoforms, PDE4D4 and PDE4D8, had no effect on neurite length, which can be explained by the observation that these forms are not expressed in HT22 cells [1].

The role of PDE4D in regulating neurite outgrowth was supported by the localization of PDE4D protein in growth cones and the fact that many of known PDE4D-interacting proteins are involved in neuron projection development. As PDE4D was also found to localize to Microtubles in neurons of the macaque prefrontal cortex, which could be reason for its significance in cognitive ability when modulated.

The mean log2 microarray PDE4D mRNA expression averaged across probes within each subject in pyramidal cells (5.77 ± 0.54) was significantly ∼3-fold higher (p < 0.001; q < 0.001) compared to PV interneurons (4.26 ± 0.69) in human dlPFC layer III, indicating significantly greater expression of PDE4D mRNA in pyramidal cells from the same subjects. [1]

Immunocytochemistry and transfection studies demonstrate colocalization of PDE4D and myomegalin in the Golgi/centrosomal area of cultured cells, and in sarcomeric structures of skeletal muscle. Myomegalin expressed in COS-7 cells coimmunoprecipitated with PDE4D3 and sequestered it to particulate structures.

Based on immunocytochemistry, it was found that PDE4D is expressed in the neurite growth cones of HT22 cells [1].

Moreover, PDE4D3 can bind to the centrosome via AKAP9, thereby regulating cell cycle progression. Thus, genetic knockdown of PDE4D3 likely promoted cAMP-PKA signaling in both the perinuclear and centrosomal regions, which may have halted cell cycle progression and promoted neurite growth.

Inhibition

For more information about PDE4D inhibition, check out the following writeup: