Phosphodiesterase 10A, isoform 2 (PDE10A2) (PDE10A2)

Phosphodiesterase 10A (PDE10A) is a dual-substrate enzyme that plays a critical role in regulating the intracellular levels of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), with a significantly higher affinity for cAMP (PubMed, 2020). The PDE10A2 isoform is a specific splice variant characterized by its membrane association, which is facilitated by N-terminal palmitoylation at Cys-11, distinguishing it from the cytosolic PDE10A1 isoform (UniProt). It is highly and almost exclusively expressed in the medium spiny neurons of the striatum, where it plays a pivotal role in modulating dopaminergic signaling and the balance between the direct and indirect basal ganglia pathways (NIH, 2021). By regulating the magnitude and duration of cyclic nucleotide signaling, PDE10A2 influences key processes such as synaptic plasticity, motor coordination, and cognitive function. Dysregulation of this enzyme is associated with several neuropsychiatric and neurodegenerative disorders, including schizophrenia and Huntington's disease, as well as metabolic conditions like obesity and certain cancers (PubMed, 2023). Pharmacological inhibition of PDE10A2 increases intracellular cAMP and cGMP levels, leading to the activation of protein kinase A (PKA) and protein kinase G (PKG) signaling, which has been explored as a therapeutic strategy to improve symptoms in these conditions. Several selective inhibitors, such as TAK-063 and MK-8189, have advanced to clinical trials, demonstrating potential in addressing the positive, negative, and cognitive symptoms of schizophrenia (ClinicalTrials.gov).

Other names

PDE10A2PDE10A1HSPDE10AADSD2IOLODPhosphodiesterase 10A

Inhibition of the dual-substrate enzyme PDE10A, which prevents the hydrolysis of cAMP and cGMP, thereby increasing their intracellular concentrations and enhancing downstream PKA and PKG signaling pathways in the striatum.