Subcellular Organization of the cAMP Signaling Pathway

Zaccolo, Manuela; Zerio, Anna; Lobo, Miguel J

doi:10.1124/pharmrev.120.000086

Cited by 171 publications

(173 citation statements)

References 463 publications

(605 reference statements)

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“…However, there is also evidence that spatial differences in signaling may be critically involved in such specific downstream effects. Compartmentalization of cAMP and of receptor-mediated cAMP signals has in fact been suggested for decades and by several lines of evidence, including our own previous work (10)(11)(12)(13)(14). This effect was directly visualized in adult murine CMs by means of local cAMP readouts using fluorescence biosensors and local stimulation of the receptors using a scanning probe delivery method (15).…”

mentioning

confidence: 87%

Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes

Bathe-Peters

Gmach

Boltz

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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A key question in receptor signaling is how specificity is realized, particularly when different receptors trigger the same biochemical pathway(s). A notable case is the two β‐adrenergic receptor (β‐AR) subtypes, β1 and β2, in cardiomyocytes. They are both coupled to stimulatory Gs proteins, mediate an increase in cyclic adenosine monophosphate (cAMP), and stimulate cardiac contractility; however, other effects, such as changes in gene transcription leading to cardiac hypertrophy, are prominent only for β1‐AR but not for β2-AR. Here, we employ highly sensitive fluorescence spectroscopy approaches, in combination with a fluorescent β‐AR antagonist, to determine the presence and dynamics of the endogenous receptors on the outer plasma membrane as well as on the T-tubular network of intact adult cardiomyocytes. These techniques allow us to visualize that the β2‐AR is confined to and diffuses within the T-tubular network, as opposed to the β1‐AR, which is found to diffuse both on the outer plasma membrane as well as on the T-tubules. Upon overexpression of the β2‐AR, this compartmentalization is lost, and the receptors are also seen on the cell surface. Such receptor segregation depends on the development of the T-tubular network in adult cardiomyocytes since both the cardiomyoblast cell line H9c2 and the cardiomyocyte-differentiated human-induced pluripotent stem cells express the β2‐AR on the outer plasma membrane. These data support the notion that specific cell surface targeting of receptor subtypes can be the basis for distinct signaling and functional effects.

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mentioning

confidence: 87%

Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes

Bathe-Peters

Gmach

Boltz

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Given the central role of this signaling pathway in many cellular processes, the activation of downstream targets is spatiotemporally regulated. This is achieved in a number of ways: via controlling the generation of cAMP by adenylyl cyclases, by regulating cAMP degradation through phosphodiesterases and by the subcellular targeting of cAMP effector proteins with the help of a number AKAP proteins (Zaccolo et al 2021). The cAMP effector proteins PKA, EPAC, and hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) have been well characterized in neurons (Kelly 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Subcellular compartment-specific nanodomain signaling complexes are formed in cells with the help of multiple A-kinase anchor proteins (AKAPs) (Bauman et al 2004), which bind cAMP effector proteins such as protein kinase A (PKA) or exchange factor directly activated by cAMP (EPAC), adenylyl cyclases, phosphodiesterases (PDEs) and target proteins (Houslay 2010;Schleicher and Zaccolo 2020;Zaccolo et al 2021). The concerted actions of these proteins lead to the transient activation of downstream molecular targets such as the α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor or the voltage-gated calcium channel Ca V 1.2 in response to specific patterns of synaptic activity (Patriarchi et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Mice lacking the cAMP effector protein POPDC1 show enhanced hippocampal synaptic plasticity

Shetty

Ris

Schindler

et al. 2021

Preprint

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Extensive research has uncovered diverse forms of synaptic plasticity and a wide array of molecular signaling mechanisms that act as positive or negative regulators. Specifically, cAMP-dependent signaling pathways have been crucially implicated in long-lasting synaptic plasticity. In this study, we examine the role of POPDC1 (or BVES), a cAMP effector protein expressed in brain, in modulating hippocampal synaptic plasticity. Unlike other cAMP effectors, such as PKA and EPAC, POPDC1 is membrane-bound and the sequence of the cAMP-binding cassette differs from canonical cAMP-binding domains. These properties suggest that POPDC1 may have a unique role in cAMP-mediated signaling underlying synaptic plasticity. Our results show that POPDC1 is enriched in hippocampal synaptoneurosomes. Acute hippocampal slices from Popdc1 knockout (KO) mice exhibit enhanced long-term potentiation (LTP) induced by a variety of stimulation paradigms, particularly in response to weak stimulation paradigms that in slices from wildtype mice induce only transient LTP. Furthermore, Popdc1 KO mice did not display any further enhancement in forskolin-induced LTP observed following inhibition of phosphodiesterases (PDEs), suggesting a possible modulation of cAMP-PDE signaling by POPDC1. Taken together, these data reveal POPDC1 as a novel player in the regulation of hippocampal synaptic plasticity and as a potential target for cognitive enhancement strategies.

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“…Further studies using specific siRNA and small molecule inhibitors are required to determine the PDE subtype(s) responsible for the temperature sensitivity of NE-induced cAMP signaling. Of note, recent studies advanced our understanding of cAMP signaling by revealing that distinct intracellular cAMP pools have specific signaling properties (Zaccolo et al, 2021). Different intracellular expression patterns of distinct PDE subtypes contribute to these cytosolic cAMP pools.…”

Section: Discussionmentioning

confidence: 99%

Physiological Temperature Changes Fine-Tune β₂- Adrenergic Receptor-Induced Cytosolic cAMP Accumulation

Faro¹,

Boekhoff²,

Gudermann³

et al. 2021

Mol Pharmacol

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Subcellular Organization of the cAMP Signaling Pathway

Cited by 171 publications

References 463 publications

Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes

Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes

Mice lacking the cAMP effector protein POPDC1 show enhanced hippocampal synaptic plasticity

Physiological Temperature Changes Fine-Tune β₂- Adrenergic Receptor-Induced Cytosolic cAMP Accumulation

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Subcellular Organization of the cAMP Signaling Pathway

Cited by 171 publications

References 463 publications

Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes

Visualization of β-adrenergic receptor dynamics and differential localization in cardiomyocytes

Mice lacking the cAMP effector protein POPDC1 show enhanced hippocampal synaptic plasticity

Physiological Temperature Changes Fine-Tune β2- Adrenergic Receptor-Induced Cytosolic cAMP Accumulation

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Product

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Physiological Temperature Changes Fine-Tune β₂- Adrenergic Receptor-Induced Cytosolic cAMP Accumulation