Underpinning compartmentalised cAMP through targeted cAMP breakdown

Neuroscience and Molecular Pharmacology, FBLS, University of Glasgow, University Avenue, Glasgow, G12 8QQ, Scotland, UK.
Trends in Biochemical Sciences (Impact Factor: 11.23). 10/2009; 35(2):91-100. DOI: 10.1016/j.tibs.2009.09.007
Source: PubMed


It is becoming increasingly apparent that spatial regulation of cell signalling processes is critical to normal cellular function. In this regard, cAMP signalling regulates many pivotal cellular processes and has provided the paradigm for signal compartmentalization. Recent advances show that isoforms of the cAMP-degrading phosphodiesterase-4 (PDE4) family are targeted to discrete signalling complexes. There they sculpt local cAMP gradients that can be detected by genetically encoded cAMP sensors, and gate the activation of spatially localized signalling through sequestered PKA and EPAC sub-populations. Genes for these important regulatory enzymes are linked to schizophrenia, stroke and asthma, thus indicating the therapeutic potential that selective inhibitors could have as anti-inflammatory, anti-depressant and cognitive enhancer agents.

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    • "cAMP is a second messenger that plays an important role in many biological processes (Grahame Hardie, 2014), including the activation of protein kinases (Kim et al., 2014) and mediating the effects of various hormones and sex-steroids (Simoncini and Genazzani, 2003). cAMP is decomposed to AMP by phosphodiesterase (Houslay, 2010). "
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    ABSTRACT: The consistency of the cervical mucus changes with the reproductive cycle, which we hypothesized involved changing levels of cystic fibrosis transmembrane regulator (CFTR), adenylate cyclase (AC), and cyclic adenosine mono-phosphate (cAMP). We therefore measured the abundance of each in the rat cervix under estrogen and progesterone influence to determine if the activity of these components could explain the changes in the consistency of cervical mucus. Ovariectomised adult female rats were treated with three days of either estrogen (1 μg/kg/day) or progesterone (20 mg/kg/day), or three days of estrogen followed by two days of either vehicle or progesterone or estrogen plus progesterone. In some groups, mifepristone (7 mg/kg/day) was concurrently given with progesterone. Animals were then sacrificed, and the cervix was harvested for protein and mRNA expression analyses by Western blot and real-time PCR, respectively. The distribution of proteins was investigated by immunohistochemistry, and levels of cAMP were determined by enzyme-linked immunosorbent assay (ELISA). Cftr mRNA, AC protein, and cAMP levels in cervical homogenates as well as the tissue distribution of CFTR and AC in endocervical epithelia were highest under estrogen influence; the opposite pattern was seen under progesterone influence. Cervical lumen circumference was highest under estrogen and lowest under progesterone. The effects of progesterone were antagonized by mifepristone. Therefore, increased abundance of CFTR, AC, and cAMP under estrogen influence could account for the increased fluid accumulation within the cervical lumen, which would contribute to lower cervical mucus consistency, whereas progesterone reverses this effect at the molecular and organ level. Mol. Reprod. Dev. 9999: 1-12, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Molecular Reproduction and Development 05/2015; 82(6). DOI:10.1002/mrd.22496 · 2.53 Impact Factor
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    • "The duration and strength of signals produced by cAMP effectors is often heavily influenced by action of a super-family of enzymes that has evolved to degrade cyclic-nucleotides, the phosphodiesterases (PDEs) [2]. Of particular interest is the PDE4 family of enzymes, which is made up of over 25 different isoforms, many of which have important, non-redundant functions [3]. Often, the function of a particular PDE4 isoform is conferred by its unique N-terminal, which acts as a ''postcode'' to anchor PDE4 enzymes to discrete intracellular domains where they sculpt signal-specific cAMP gradients . "
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    ABSTRACT: The cyclic AMP phosphodiesterases type 4 (PDE4s) are expressed in a cell specific manner, with intracellular targeting directed by unique N-terminal anchor domains. All long form PDE4s are phosphorylated and activated by PKA phosphorylation within their upstream conserved region 1 (UCR1). Here, we identify and characterise a novel PKA site (serine 42) within the N-terminal region of PDE4D7, an isoform whose activity is known to be important in prostate cancer progression and ischemic stroke. In contrast to the UCR1 site, PKA phosphorylation of the PDE4D7 N-terminus appears to occur constitutively and inhibits PDE4 activity to allow cAMP signalling under basal conditions.
    FEBS Letters 02/2015; 276(6). DOI:10.1016/j.febslet.2015.02.004 · 3.17 Impact Factor
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    • "This enzyme is a member of the PDE4 family of phosphodiesterases, comprising N25 isoforms encoded by 4 genes in mammals. The different isoforms of PDE4 interact with an array of signalling proteins, such as protein kinases and scaffolding proteins, and they are sequestered in this way to distinct subcellular locales, predominantly by interactions mediated through their isoformspecific N-termini [13]. This localisation allows cAMP signalling compartmentation , where the stimulus cAMP, its effectors such as cAMPdependent protein kinase (PKA) and substrates thereof are brought closely together in one protein complex. "
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    ABSTRACT: p62, also known as SQSTM1, is a multi-domain signalling scaffold protein involved in numerous critical cellular functions such as autophagy, apoptosis and inflammation. Crucial interactions relevant to these functions are mediated by the N-terminal Phox and Bem1p (PB1) domain, which is divided into two interaction surfaces, one of predominantly acidic and one of basic character. Most known interaction partners, including atypical protein kinase C (aPKC), bind to the basic surface, and acidic-basic interactions at this interface also allow for p62 homopolymerisation. We identify here that the coupling of p62 to the cAMP signalling system is conferred by both the direct binding of cAMP degrading phosphodiesterase-4 (PDE4) to the acidic surface of the p62 PB1 domain and the phosphorylation of the basic surface of this domain by cAMP-dependent protein kinase (PKA). Such phosphorylation is a previously unknown means of regulating PB1 domain interaction partnerships by disrupting the interaction of p62 with basic surface binding partners, such as aPKCs, as well as p62 homopolymerisation. Thus, we uncover a new regulatory mechanism that connects cAMP signalling with the p62 multi-domain signalling scaffold and autophagy cargo receptor protein.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 08/2014; 1843(11). DOI:10.1016/j.bbamcr.2014.07.021 · 5.02 Impact Factor
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