The disrupted in schizophrenia 1 ( DISC1 ) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role in the disorder is unknown. Here we report that the gene encoding phosphodiesterase 4B ( PDE4B ) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The PDEs inactivate adenosine 3′,5′-monophosphate (cAMP), a second messenger implicated in learning, memory, and mood. We show that DISC1 interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and an increase in PDE4B activity. We propose a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.

Catecholamines signal through the β ₂ -adrenergic receptor by promoting production of the second messenger adenosine 3′,5′-monophosphate (cAMP). The magnitude of this signal is restricted by desensitization of the receptors through their binding to β-arrestins and by cAMP degradation by phosphodiesterase (PDE) enzymes. We show that β-arrestins coordinate both processes by recruiting PDEs to activated β ₂ -adrenergic receptors in the plasma membrane of mammalian cells. In doing so, the β-arrestins limit activation of membrane-associated cAMP-activated protein kinase by simultaneously slowing the rate of cAMP production through receptor desensitization and increasing the rate of its degradation at the membrane.

It is well known that sleep deprivation can have cognitive consequences, including learning and memory deficits, but the mechanisms by which sleep deprivation affects brain function remain unknown. New experiments identify the cyclic AMP pathway as a functional target of sleep deprivation, specifically the impairment of cAMP/PKA-based plasticity in the hippocampus. Rescuing cAMP signalling using phosphodiesterase inhibitors also rescues the memory deficits, pointing to cAMP/PKA signalling enhancers as a possible therapeutic approach to counteract the cognitive effects of lost sleep. Sleep deprivation can have adverse cognitive effects, with one of the major consequences on the brain being memory deficits in learning models that are dependent on the hippocampus. A molecular mechanism by which brief sleep deprivation alters hippocampal function is now identified in mice; it involves the impairment of cyclic-AMP- and protein-kinase-A-dependent forms of synaptic plasticity. Millions of people regularly obtain insufficient sleep1. Given the effect of sleep deprivation on our lives, understanding the cellular and molecular pathways affected by sleep deprivation is clearly of social and clinical importance. One of the major effects of sleep deprivation on the brain is to produce memory deficits in learning models that are dependent on the hippocampus2,3,4,5. Here we have identified a molecular mechanism by which brief sleep deprivation alters hippocampal function. Sleep deprivation selectively impaired 3′, 5′-cyclic AMP (cAMP)- and protein kinase A (PKA)-dependent forms of synaptic plasticity6 in the mouse hippocampus, reduced cAMP signalling, and increased activity and protein levels of phosphodiesterase 4 (PDE4), an enzyme that degrades cAMP. Treatment of mice with phosphodiesterase inhibitors rescued the sleep-deprivation-induced deficits in cAMP signalling, synaptic plasticity and hippocampus-dependent memory. These findings demonstrate that brief sleep deprivation disrupts hippocampal function by interfering with cAMP signalling through increased PDE4 activity. Thus, drugs that enhance cAMP signalling may provide a new therapeutic approach to counteract the cognitive effects of sleep deprivation.

A simple catheter disk model system was used to study the development in vitro of mixed species biofilms of Candida albicans and Staphylococcus epidermidis, two organisms commonly found in catheter-associated infections. Two strains of S. epidermidis were used: a slime-producing wild type (strain RP62A) and a slime-negative mutant (strain M7). In mixed fungal-bacterial biofilms, both staphylococcal strains showed extensive interactions with C. albicans. The susceptibility of 48-h biofilms to fluconazole, vancomycin and mixtures of the drugs was determined colorimetrically. The results indicated that the extracellular polymer produced by S. epidermidis RP62A could inhibit fluconazole penetration in mixed fungal-bacterial biofilms. Conversely, the presence of C. albicans in a biofilm appeared to protect the slime-negative staphylococcus against vancomycin. Overall, the findings suggest that fungal cells can modulate the action of antibiotics, and that bacteria can affect antifungal activity in mixed fungal-bacterial biofilms.

Phosphorylation of the β ₂ adrenoreceptor (β ₂ AR) by cAMP-activated protein kinase A (PKA) switches its predominant coupling from stimulatory guanine nucleotide regulatory protein (G _s ) to inhibitory guanine nucleotide regulatory protein (G _i ). β-Arrestins recruit the cAMP-degrading PDE4 phosphodiesterases to the β ₂ AR, thus controlling PKA activity at the membrane. Here we investigate a role for PDE4 recruitment in regulating G protein switching by the β ₂ AR. In human embryonic kidney 293 cells overexpressing a recombinant β ₂ AR, stimulation with isoprenaline recruits β-arrestins 1 and 2 as well as both PDE4D3 and PDE4D5 to the receptor and stimulates receptor phosphorylation by PKA. The PKA phosphorylation status of the β ₂ AR is enhanced markedly when cells are treated with the selective PDE4-inhibitor rolipram or when they are transfected with a catalytically inactive PDE4D mutant (PDE4D5-D556A) that competitively inhibits isoprenaline-stimulated recruitment of native PDE4 to the β ₂ AR. Rolipram and PDE4D5-D556A also enhance β ₂ AR-mediated activation of extracellular signal-regulated kinases ERK1/2. This is consistent with a switch in coupling of the receptor from G _s to G _i , because the ERK1/2 activation is sensitive to both inhibitors of PKA (H89) and G _i (pertussis toxin). In cardiac myocytes, the β ₂ AR also switches from G _s to G _i coupling. Treating primary cardiac myocytes with isoprenaline induces recruitment of PDE4D3 and PDE4D5 to membranes and activates ERK1/2. Rolipram robustly enhances this activation in a manner sensitive to both pertussis toxin and H89. Adenovirus-mediated expression of PDE4D5-D556A also potentiates ERK1/2 activation. Thus, receptor-stimulated β-arrestin-mediated recruitment of PDE4 plays a central role in the regulation of G protein switching by the β ₂ AR in a physiological system, the cardiac myocyte.