WWe show the effects of the three purine derivatives, caffeine, theophylline, and istradefylline, on the cAMP production of adenylyl cyclase 5 (ADCY5)-overexpressing cell lines. A comparison of cAMP levels was performed for ADCY5 wild-type and R418W mutant cells. ADCY5-catalyzed cAMP production was reduced with all three purines, while the most pronounced effects on cAMP reduction were observed for ADCY5 R418W mutant cells. The gain-of-function ADCY5 R418W mutant is characterized by an increased catalytic activity resulting in elevated cAMP levels, resulting in kinetic disorders or dyskinesia in patients. Based on our findings in ADCY5 cells, a slow-release formulation of theophylline was administered to a preschool aged patient with ADCY5-related dyskinesia. A striking improvement of symptoms was observed, outperforming the effects of caffeine that had previously been administered to the same patient.

The authors have declared no competing interest.

DRKS00029154

DFG (RTG 2467, project number 391498659: Intrinsically Disordered Proteins. Molecular Principles, Cellular Functions, and Diseases, RTG 2751: InCuPanC, project number 449501615, INST 271/404-1 FUGG, INST 271/405-1 FUGG, and CRC 1423, project number 421152132). The Federal Ministry for Economic Affairs and Energy (BMWi, ZIM project KK5096401SK0). Region of Saxony-Anhalt. Martin Luther University Halle-Wittenberg (Center for Structural Mass Spectrometry).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The ethics committee of the University of Leipzig was informed and approved this study. The study has been registered at the DRKS (ID: DRKS00029154).

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