PDE4 as a target for cognition enhancement

Abstract

Introduction: The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning, and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs.

Areas covered: PDE4 is the largest of the 11 mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation.

Expert opinion: PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors.

Figure 1. Members, domain organization and regulatory properties of the PDE4 family

The PDE4 family comprises four genes, PDE4A-D, and each is expressed as multiple variants. At least six PDE4A variants (PDE4A1, PDE4A4/5, PDE4A7, PDE4A8, PDE4A10 and PDE4A11), five PDE4B variants (PDE4B1-5), three PDE4C variants (PDE4C1-3), and eleven PDE4D variants (PDE4D1-11) have been reported. Shown is the domain organization of the eleven variants generated from the PDE4D gene. Domains are depicted as ‘barrels’ connected by ‘wires’ indicating linker regions. Domains functioning as targeting sequences by mediating protein/protein interactions are indicated as red striated barrels. These are generally encoded by variant-specific first exons. Phosphorylation sites for protein kinase A (PKA) and extracellular signal-regulated kinase 2 (ERK2) are depicted as cyan circles. Long and short PDE4 variants are distinguished by the complete or partial presence of the UCR1/2 module. The regions of the UCR domains that mediate dimerization of PDE4 long forms are indicated by a blue rectangle.

Figure 2. PDE4 inhibition, cAMP signaling and brain function

Scheme illustrating the signaling events linking PDE4 inhibition to improved brain function. Inhibition of PDE4 triggers an increase in cAMP which in turn exerts its downstream effects via activation of protein kinase A (PKA), exchange proteins activated by cAMP (EPACs) and cyclic nucleotide-gated (CNG) and hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels. PKA is well known to phosphorylate a range of signaling proteins including CREB (cAMP response element binding protein), synapsin, DARPP32 (dopamine- and cAMP-regulated phosphoprotein of M_r 32 kDa) and tyrosine hydroxylase (TH) and thereby modulate gene expression, ion channel function, neurotransmitter synthesis and release as well as various other signaling events that regulate memory and cognitive processes. Recent evidence suggests that EPAC is involved in many of the same signaling paradigms previously associated with PKA, suggesting that some of the established effects of PDE4 inhibitors on memory and cognition might be mediated by EPAC rather than PKA activation [147-154]. Although a role for cyclic nucleotide-regulated channels (CNG and HCN) in brain function is well established [155,156], little is known thus far about the role of PDEs in regulating the pool of cAMP that controls the function of these channels. NT, neurotransmitter; AC, adenylyl cyclase; G_sPCR, G_s protein-coupled receptor; G_iPCR, G_i protein-coupled receptor; βAR, β-adrenergic receptor; αAR, α-adrenergic receptor; DR, dopamine receptor; 5HTR, serotonin type 1D receptor