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Cyclic amp3/10/2023 ![]() Although all transmembrane ACs are activated by the binding of GTP-bound G sα or the AC agonist forskolin, they differ in their molecular regulation and expression ( Hanoune and Defer, 2001 Willoughby and Cooper, 2007). There are several types of ACs that differ in their distinct patterns of molecular regulation and tissue-specific expression ( Hanoune and Defer, 2001 Willoughby and Cooper, 2007). In contrast, they predicted that if PDEs were uniformly distributed, PDEs expressed at biochemically reasonable values would be insufficient to generate cAMP gradients ( Chen et al., 2008).ĬAMP is synthesized by ACs from ATP. (2008) developed models with varying localization of PDEs, showing that colocalization of PDEs with ACs provided optimal compartmentation. (2011) further extended this model (as discussed below), predicting that PDE3 plays the dominant role in regulation of baseline caveolar and cytosolic. This is a helpful model prediction because it is difficult to experimentally dissect PDE isoform localization from their distinct kinetic and regulatory properties. Their model predicted that heterogeneous PDE localization (not the PDE isoform per se) was critical for maintaining cAMP gradients under basal and stimulated conditions ( Iancu et al., 2007). (2007) developed a multi-compartmental model of cAMP signaling in cardiac myocytes, including PDE2, PDE3, and PDE4 isoforms, and distinct sarcolemmal domains. (2006) measured and modeled β-adrenergic–stimulated gradients of cAMP/PKA signaling between sarcolemma and cytosol, predicting that the measured time delays from sarcolemmal to cytosolic PKA activity were insensitive to PDE localization or mobility unless cAMP diffusion rates were slowed. Several models have examined how PDE localization contributes to cAMP compartmentation. Similarly, PDE4 plays a dominant role regulating subsarcolemmal cAMP, as measured by CNG channels expressed in cardiac myocytes ( Rochais et al., 2004). Measurement of cAMP signals using PKA-based fluorescence resonance energy transfer biosensors revealed that PDE4 dominates regulation of both basal and β-adrenergic–stimulated cAMP, whereas PDE3 dominated cAMP responses to forskolin in cardiac myocytes ( Mongillo et al., 2004). Although PDE3 contains membrane-binding domains and appears to target to intracellular membranes, PDE4 is primarily bound to A kinase–anchoring proteins (AKAPs) ( Francis et al., 2011 Kapiloff et al., 2014) and localized in striated patterns, colocalized with either sarcomeric M-line or Z-lines ( Mongillo et al., 2004). In most cells, PDE3 and PDE4 are the dominant PDE isoforms for cAMP degradation ( Francis et al., 2011). The expression of multiple PDE isoforms and their localization to various cellular structures suggest that PDEs may regulate distinct cAMP compartments. Simulations with realistic neuronal geometries ( Neves et al., 2008) have also explained how PDEs contribute to experimentally observed cAMP gradients between dendrites and the cell body ( Bacskai et al., 1993). (2006) modeled cAMP and PKA signaling with image-based cardiac myocyte geometry, predicting that PDE regulated the magnitude of cytosolic cAMP/PKA gradients. A subsequent experimental and computational study from their group further demonstrated that the enhanced PDE activity was caused by PKA-mediated PDE phosphorylation ( Rich et al., 2007), agreeing with previous experimental evidence of negative feedback by PKA on ( Rochais et al., 2004). (2001) predicted that prostaglandin E1 (PGE1)-stimulated PDE activity was critical for quantitatively explaining the transient plasma membrane cAMP signals measured experimentally. Nearly all computational models have predicted a quantitatively important role of PDE-mediated cAMP degradation in the formation of cAMP gradients (see Table 1). A limitation to these biochemical approaches is that they destroy the intact cellular environment, and particulate fractions contain a wide range of membranes, sarcomeres, and organelles. Although activation of both β-adrenergic and prostaglandin receptors increased soluble cAMP and PKA activity in heart homogenates, only β-adrenergic receptors elevated cAMP and PKA in the particulate fraction ( Hayes et al., 1980) and triggered downstream increases in contractility and glycogen metabolism ( Brunton et al., 1979). Increasing cAMP synthesis or blocking its degradation caused disproportionate increases in the soluble fraction ( Corbin et al., 1977). (1977) isolated particulate and soluble fractions of rabbit heart homogenates, finding that about half of the total cAMP content was bound to PKA regulatory subunit in the particulate fraction. ![]() The initial measurements of cAMP compartmentation were performed by cellular fractionation and radioimmunoassay.
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