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The olfactory system receives extensive serotonergic inputs from the dorsal raphe, a nucleus involved in control of behavior, regulation of mood, and modulation of sensory processing. Although many studies have investigated how serotonin modulates the olfactory bulb, few have focused on the anterior piriform cortex (aPC), a region important for olfactory learning and encoding of odor identity and intensity. Specifically, the mechanism and functional significance of serotonergic modulation of the aPC remain largely unknown. Here we used pharmacologic, optogenetic, and fiber photometry techniques to examine the serotonergic modulation of neural activity in the aPC in vitro and in vivo. We found that serotonin (5-HT) reduces the excitability of pyramidal neurons directly via 5-HT2C receptors, phospholipase C, and calcium-activated potassium (BK) channels. Furthermore, endogenous serotonin attenuates odor-evoked calcium responses in aPC pyramidal neurons. These findings identify the mechanism underlying serotonergic modulation of the aPC and shed light on its potential role. [ABSTRACT FROM AUTHOR]

Cyclic nucleotide phosphodiesterase (POE) isoforms can influence disease pathogenesis and be novel therapeutic targets. Because lower cAMP levels may contribute to the decreased apoptosis that occurs in chronic lymphocytic leukemia (CLL), we assessed the expression levels of POE isoforms in peripheral blood mononuclear cells (PBMC) of healthy adults and patients with CLL. We found a unique POE mRNA signature in CLI: higher levels than in normal PBMC of PDE7B (increased ≈23-fold) and lower levels of PDE3B, 4D, 5A, and 9A mRNA (each decreased ≈30-fold). Increased POE7B mRNA in CLL correlates with a 10-fold-higher expression of PDE7B protein and results in an increased contribution of PDE7 to total PDE activity. Consistent with the higherlevel of PDE7B expression, inhibitors of PDE7 (BRL-50481, IR-202) and a dual PDE4/PDE7 inhibitor (IR-284) selectively increase apoptosis in CLI cells compared with normal PBMC or B cells. Apoptosis of CLI cells promoted by inhibitors of PDE7 and PDE4I7 is attenuated by PKA inhibition, occurs via a mitochondrial-dependent process, and is associated with increased cAMP accumulation and down-regulation of the antiapoptotic protein survivin and of PDE7B. The increase in PDE7B expression and PDE7 inhibitor-promoted apoptosis implicates PDE7B as a drug target in CLI. Our findings identify a unique PDE signature in CLL and illustrate the utility of broad analyses of POE isoform expression in human disease. [ABSTRACT FROM AUTHOR]

Although a substantial number of hormones and drugs increase cellular CAMP levels, the global impact of CAMP and its major effector mechanism, protein kinase A (PKA). on gene expression is not known. Here we show that treatment of murine wild-type 549 lymphoma cells for 24 h with 8-(4-chlorophenylthio)-cAMP (8-CPT- CAMP), a PKA-selective cAMP analog, alters the expression of ≈4,500 of ≈ 13,600 unique genes. By contrast, gene expression was unaltered in Kin- 549 cells (that lack PKA) incubated with 8-CPT- CAMP. Changes in mRNA and protein expression of several cell- cycle regulators accompanied cAMP-induced G1-phase cell-cycle arrest of wild-type S49 cells. Within 2 h, 8-CPT-cAMP altered expression of 152 genes that contain evolutionarily conserved cAMP-response elements within 5 kb of transcriptional start sites, including the circadian clock gene Pen. Thus, CAMP through its activation of PKA produces extensive transcriptional regulation in eukaryotic cells. These transcriptional networks include a primary group of cAMP-response element-containing genes and secondary networks that include the circadian clock. [ABSTRACT FROM AUTHOR]