Phosphodiesterase 1 Bridges Glutamate Inputs with NO- and Dopamine-Induced Cyclic Nucleotide Signals in the Striatum

Abstract

The calcium-regulated phosphodiesterase 1 (PDE1) family is highly expressed in the brain, but its functional role in neurones is poorly understood. Using the selective PDE1 inhibitor Lu AF64196 and biosensors for cyclic nucleotides including a novel biosensor for cGMP, we analyzed the effect of PDE1 on cAMP and cGMP in individual neurones in brain slices from male newborn mice. Release of caged NMDA triggered a transient increase of intracellular calcium, which was associated with a decrease in cAMP and cGMP in medium spiny neurones in the striatum. Lu AF64196 alone did not increase neuronal cyclic nucleotide levels, but blocked the NMDA-induced reduction in cyclic nucleotides indicating that this was mediated by calcium-activated PDE1. Similar effects were observed in the prefrontal cortex and the hippocampus. Upon corelease of dopamine and NMDA, PDE1 was shown to down-regulate the D1-receptor mediated increase in cAMP. PDE1 inhibition increased long-term potentiation in rat ventral striatum, showing that PDE1 is implicated in the regulation of synaptic plasticity. Overall, our results show that PDE1 reduces cyclic nucleotide signaling in the context of glutamate and dopamine coincidence. This effect could have a therapeutic value for treating brain disorders related to dysfunctions in dopamine neuromodulation.

Pivotal role of PDE10A in the integration of dopamine signals in mice striatal D1 and D2 medium-sized spiny neurones

“…PDE1B has a Km of 33 µM for cAMP (Poppe et al, 2008). Our previous work showed that, in D1 MSNs, PDE1 efficiently degrades high cAMP levels in the context of dopamine and NMDA coincidence (Betolngar et al, 2019). In the present work, intracellular calcium was not increased and therefore PDE1B did not contribute to the effects we analysed here.…”

A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated with Schizophrenia

“…In addition, it might be related to the fact that PDE1B and PDE1A enzymes prefer cGMP (K m 5 1.2-5.9 mM for PDE1B; K m 5 2.6-3.5 mM for PDE1A) to cAMP (K m 5 10-24 mM for PDE1B; K m 5 72.7-124 mM for PDE1A) (Bender and Beavo, 2006). However, it is worth mentioning that the brain's cyclic nucleotide content is not a highly sensitive indicator, especially considering the on-demand nature of PDE1 enzyme activation by phasic Ca 21 influx (Grauer et al, 2009;Wennogle et al, 2017;Pekcec et al, 2018;Betolngar et al, 2019). Strick et al (2010) have reported that immediate early gene c-fos expression is regulated by the cAMP pathway but not the cGMP pathways after administration of an inhibitor of PDE10A, which is another striatum-enriched dual-substrate PDE isoform.…”

“…The regulation of D 2 receptor downstream signaling by DSR-141562 might be involved in its antipsychotic efficacy. Indeed, Betolngar et al (2019) have reported that PDE1 inhibitor suppresses the N-methyl-D-aspartate-induced decrease in cAMP not only in D 1 receptor-expressing but also D 2 receptor-expressing striatal neurons in vitro. Thus, the antipsychotic mechanism of DSR-141562, especially the contribution of the D 2 receptor-expressing indirect pathway, remains to be evaluated.…”

“…Interestingly, PDE1B is colocalized with dopamine D 1 and/or D 2 receptors in the striatal and prefrontal cortical neurons in rats and humans (Polli and Kincaid, 1994;Yan et al, 1994;Pekcec et al, 2018). Furthermore, Betolngar et al (2019) have shown that PDE1 regulates cyclic nucleotide signaling in the context of glutamate and dopamine coincidence. The Ca 21 influx via N-methyl-D-aspartate receptors, which are glutamategated Ca 21 channels, transiently activate PDE1B in dopamine D 1 or D 2 receptor-expressing medium spiny neurons.…”

Flexible mixture model approaches that accommodate footprint size variability for robust detection of balancing selection

“…In fact, the high-scoring peak we observed on this gene happens to locate around the exons that are spliced out in some variants ( Figure S22). Studies have demonstrated the relation of this gene to brain development (Yan et al, 1994), mood and cognitive disorders (Xu et al, 2011;Martinez and Gil, 2013;Pekcec et al, 2018;Betolngar et al, 2019), and hypertension (Kimura et al, 2017). Meanwhile, the PDE1A protein is also a conserved component of mammalian spermatozoa Vasta et al, 2005), and is involved in the movement of flagella-organelles featured in both animal sperms and some protozoa such as the Trypanosoma parasites (Oberholzer et al, 2007), with which the endemic geographical regions are avoided by bonobos (Inogwabini and Leader-Williams, 2012).…”