Pharmaceutical Research & Development (Track)


Azza Altawashi and Christoph Gehring

King Abdullah University of Science and Technology, Division of Chemical and Life Sciences and Engineering, Jeddah, Saudi Arabia


Cyclic adenosine 3'',5''-monophosphate (cAMP) is a key regulator of many cellular processes, including in the neuronal system, and its activity is tuned by Phosphodiesterase (PDE) activation. Further, the Coiled-coil and C2 domain containing 1A (CC2D1A) protein was shown to regulate the cAMP-PKA pathway and a human deletion mutation causes Non Syndromic Mental Retardation (NSMR). Here we demonstrate that CC2D1A co-localizes with PDE4D before and after cAMP stimulation. In CC2D1A mouse mutant cells, the absence of 3 DM14 domains results in constitutive phosphorylation of PDE4D Serine 13 (S(13)) via the cAMP-dependent protein kinase A (PKA) and consequent hyperactivity. Suppressing PDE4D hyperactivity rescued the cAMP response element-binding protein (CREB) defect in the mouse mutant cells. In summary, our findings demonstrate that CC2D1A interacts directly with PDE4D regulating its activity and thereby fine-tuning cAMP-dependent downstream signaling. We propose that the CC2D1A mutation phenotype in NSMR is caused by a disturbed cAMP homeostasis in neuronal cells.