Adenosine Kinase: Cytoplasmic and Nuclear Isoforms

Adenosine is an endogenous anticonvulsant, which is inversely linked to the expression levels of adenosine kinase (ADK), a ribokinase that metabolizes adenosine into AMP. ADK exists as two distinct isoforms, with unique cellular compartmentalization and functions. The short isoform (ADK-S) is localized primarily in the cytoplasm of astrocytes, where it controls, in conjunction with equilibrative adenosine transporters, the extracellular levels of adenosine and hence adenosine receptor-mediated mechanisms. On the other hand, the long isoform of ADK (ADK-L) is localized in the nucleus of astrocytes and a subset of neurons, where it regulates adenosine receptor independent epigenetic mechanisms. Overexpression of ADK-S was sufficient to generate spontaneous electrographic seizures, whereas increased ADK-L has been associated with epileptogenesis. Hence, targeting specific ADK isoforms is a rational approach for the suppression of seizures and the development of epilepsy. Systemic adenosine augmentation therapies are effective in seizure suppression, although accompanied by widespread cardiovascular side effects. The refinement of therapeutic administration strategies, the development of isoform-specific ADK inhibitors, or a combination of the two, will enable the formulation of more selective therapies for epilepsy and its prevention. Therapeutic tools to achieve focal adenosine augmentation, such as engineered stem cells and silk-based polymers, demonstrate robust protection from induced and spontaneous seizures. Metabolic therapies such as the ketogenic diet therapy have also been indicated to prevent disease progression via epigenetic mechanisms mediated by ADK. Small-molecule, ADK isoform-specific inhibitors are now in development with the goal to translate ADK-based therapies into clinical applications.