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PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization.

ABSTRACT: cAMP is a second messenger that controls many key cellular functions. The only way to inactivate cAMP is to degrade it through the action of cAMP phosphodiesterases (PDEs). PDEs are thus poised to play a key regulatory role. PDE4 cAMP-specific phosphodiesterases appear to have specific functions with selective inhibitors serving as potent anti-inflammatory agents. The recent elucidation of the structure of the PDE4 catalytic unit allows for molecular insight into the mode of catalysis as well as substrate and inhibitor selectivity. The four PDE4 genes encode over 16 isoforms, each of which is characterized by a unique N-terminal region. PDE4 isoforms play a pivotal role in controlling functionally and spatially distinct pools of cAMP by virtue of their unique intracellular targeting. Targeting occurs by association with proteins, such as arrestins, SRC family tyrosyl kinases, A-kinase anchoring proteins ('AKAPs') and receptor for activated C kinase 1 ('RACK1'), and, in the case of isoform PDE4A1, by a specific interaction (TAPAS-1) with phosphatidic acid. PDE4 isoforms are 'designed' to be regulated by extracellular-signal-related protein kinase (ERK), which binds to anchor sites on the PDE4 catalytic domain that it phosphorylates. The upstream conserved region 1 (UCR1) and 2 (UCR2) modules that abut the PDE4 catalytic unit confer regulatory functions by orchestrating the functional outcome of phosphorylation by cAMP-dependent protein kinase ('PKA') and ERK. PDE4 enzymes stand at a crossroads that allows them to integrate various signalling pathways with that of cAMP in spatially distinct compartments.

SUBMITTER: Houslay MD

PROVIDER: S-EPMC1223165 | biostudies-other | 2003 Feb

REPOSITORIES: biostudies-other

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Project description:AimsCardiac ?-adrenergic receptor (?AR) signalling is susceptible to heterologous desensitization by different neurohormonal stimuli in clinical conditions associated with heart failure. We aim to examine the underlying mechanism of cross talk between ?ARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists.Methods and resultsRat ventricular cardiomyocytes were used to determine heterologous phosphorylation of ?ARs under a series of GPCR agonists. Activation of Gs-coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and Gq-coupled ?1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of ?1AR and ?2AR at putative protein kinase A (PKA) phosphorylation sites; but activation of Gi-coupled ?2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote ?2AR phosphorylation effectively inhibit ?AR agonist isoproterenol-induced PKA phosphorylation of phospholamban and contractile function in ventricular cardiomyocytes. Heterologous GPCR stimuli have minimal to small effect on isoproterenol-induced ?2AR activation and G-protein coupling for cyclic adenosine monophosphate (cAMP) production. However, these GPCR stimuli significantly promote phosphorylation of phosphodiesterase 4D (PDE4D), and recruit PDE4D to the phosphorylated ?2AR in a ?-arrestin 2 dependent manner without promoting ?2AR endocytosis. The increased binding between ?2AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in ?2AR, inhibition of PDE4, or genetic ablation of PDE4D or ?-arrestin 2 abolishes this heterologous inhibitory effect. Ablation of ?-arrestin 2 or PDE4D gene also rescues ?-adrenergic stimuli-induced myocyte contractile function.ConclusionsThese data reveal essential roles of ?-arrestin 2 and PDE4D in a common mechanism for heterologous desensitization of cardiac ?ARs under hormonal stimulation, which is associated with impaired cardiac function during the development of pathophysiological conditions.

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PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization.

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