Abstract
PDE9A is a cGMP-specific phosphodiesterase expressed in neurons throughout the brain that has attracted attention as a therapeutic target to treat cognitive disorders. Indeed, PDE9A inhibitors are under evaluation in clinical trials as a treatment for Alzheimer’s disease and schizophrenia. However, little is known about the cGMP signaling cascades regulated by PDE9A. Canonical cGMP signaling in brain follows the activation of neuronal nitric oxide synthase (nNOS) and the generation of nitric oxide, which activates soluble guanylyl cyclase and cGMP synthesis. However, we show that in mice, PDE9A regulates a pool of cGMP that is independent of nNOS, specifically, and nitric oxide signaling in general. This PDE9A-regulated cGMP pool appears to be highly compartmentalized and independent of cGMP pools regulated by several PDEs. These findings provide a new foundation for study of the upstream and downstream signaling elements regulated by PDE9A and its potential as a therapeutic target for brain disease.
Highlights
PDE9A is a phosphodiesterase specific and with high affinity for cGMP
The results of our studies indicate that PDE9A regulates a cGMP signaling cascade that is active throughout the brain
Given that PDE9A inhibition has been found to have a number of significant neurophysiological effects and impacts cognitive function in preclinical animal models, it is of considerable interest to further investigate and characterize these PDE9A regulated signaling cascades
Summary
PDE9A is a phosphodiesterase specific and with high affinity for cGMP. This enzyme is coded by a single gene but is expressed as more than 20 isoforms arising from mRNA alternative splicing (Fisher et al, 1998; Rentero et al, 2003; Kotera and Omori, 2006). In primary cultures of rat hippocampal neurons, PDE9A inhibition enhanced neurite outgrowth and the number of synapses per neurons (Hutson et al, 2011). Two groups have reported that PDE9A inhibition facilitates induction of long-term potentiation at CA3/CA1 synapses in acute hippocampal slices (Hutson et al, 2011; Kroker et al, 2012, 2014).
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