Dynamic Regulation of cAMP Synthesis through Anchored PKA-Adenylyl Cyclase V/VI Complexes

Bauman, Andrea L.; Soughayer, Joseph S.; Nguyen, Bao Tran; Willoughby, Debbie; Carnegie, Graeme K.; Wong, Wei; Hoshi, Naoto; Langeberg, Lorene K.; Cooper, Dermot M.F.; Dessauer, Carmen W.; Scott, John D.

doi:10.1016/j.molcel.2006.07.025

Cited by 191 publications

(187 citation statements)

References 31 publications

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“…The timeframe in which St-Ht31 interrupted the inhibitory coupling suggests that this effect involves proteinprotein interaction and/or covalent modification. AKAP5 is known to directly interact with AC5 and AC6 and scaffold them to AMPA receptors (39), and AKAP5-bound RII causes phosphorylation and inhibition of these enzymes (40). Furthermore, AKAP9/Yotiao directly inhibits AC2 and AC3 (41).…”

Section: Discussionmentioning

confidence: 99%

G protein-coupled Receptor 30 (GPR30) Forms a Plasma Membrane Complex with Membrane-associated Guanylate Kinases (MAGUKs) and Protein Kinase A-anchoring Protein 5 (AKAP5) That Constitutively Inhibits cAMP Production

Broselid

Berg

Chavera

et al. 2014

Journal of Biological Chemistry

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Background: GPR30 plays important roles in cardiometabolic regulation and cancer. Results: GPR30 forms a complex with a MAGUK and AKAP5 that constitutively inhibits cAMP production independently of G i/o and retains receptors in the plasma membrane. Conclusion:The GPR30-MAGUK-AKAP5 complex mediates receptor signaling. Significance: These results present a new mechanism by which a receptor inhibits cAMP production.

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Section: Discussionmentioning

confidence: 99%

G protein-coupled Receptor 30 (GPR30) Forms a Plasma Membrane Complex with Membrane-associated Guanylate Kinases (MAGUKs) and Protein Kinase A-anchoring Protein 5 (AKAP5) That Constitutively Inhibits cAMP Production

Broselid

Berg

Chavera

et al. 2014

Journal of Biological Chemistry

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“…AKAP5 is a membrane-bound AKAP that, in addition to binding PKA, binds to PKC, calcineurin (PP2B), membraneassociated guanylate kinase protein SAP97, adenylyl cyclase V/VI, and other signaling and scaffolding proteins (4,(7)(8)(9). AKAP5-anchored complexes play a key role in regulating GPCR signaling in general and ␤-adrenergic signaling in particular.…”

mentioning

confidence: 99%

Role of AKAP79/150 Protein in β1-Adrenergic Receptor Trafficking and Signaling in Mammalian Cells

Nooh

Bahouth

2013

Journal of Biological Chemistry

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Background: AKAP79/150 scaffolds PKA, PKC, and calcineurin into networks. Results: Knockdown of AKAP79/150 in cardiac myocytes inhibited the recycling of the ␤ 1 -AR and increased ␤ 1 -AR-mediated production of cyclic AMP. Conclusion: AKAP79/150 is involved in trafficking and signaling of myocardial ␤ 1 -AR. Significance: Our results indicate that AKAP79/150 might be cardioprotective via its key role in regulating the signaling intensity of cardiac ␤ 1 -AR.

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“…Our labs previously identified a complex containing AKAP79/ 150 and type 5 adenylyl cyclase (AC), that facilitates the spatiotemporal organization of cAMP signaling (4). AKAP79 inhibits AC5 activity, while providing a mechanism for feedback inhibition via PKA phosphorylation of anchored AC5.…”

mentioning

confidence: 99%

“…Assays were performed essentially as described (4). Detailed methods can be found in SI Materials and Methods.…”

mentioning

confidence: 99%

The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain

Piggott

Bauman

Scott

et al. 2008

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

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132

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A-kinase anchoring proteins (AKAPs) influence the spatial and temporal regulation of cAMP signaling events. Anchoring of PKA in proximity to certain adenylyl cyclase (AC) isoforms is thought to enhance the phosphorylation dependent termination of cAMP synthesis. Using a combination of immunoprecipitation and enzymological approaches, we show that the plasma membrane targeted anchoring protein AKAP9/Yotiao displays unique specificity for interaction and the regulation of a variety of AC isoforms. Yotiao inhibits AC 2 and 3, but has no effect on AC 1 or 9, serving purely as a scaffold for these latter isoforms. Thus, Yotiao represents an inhibitor of AC2. The N terminus of AC2 (AC2-NT), which binds directly to amino acids 808 -957 of Yotiao, mediates this interaction. Additionally, AC2-NT and Yotiao (808 -957) are able to effectively inhibit the association of AC2 with Yotiao and, thus, reverse the inhibition of AC2 by Yotiao in membranes. Finally, disruption of Yotiao-AC interactions gives rise to a 40% increase in brain AC activity, indicating that this anchoring protein functions to directly regulate cAMP production in the brain. 2). This family of proteins functions to target PKA and other cAMP effector proteins to specific regions of the cell allowing for increased signaling specificity. Several members of this diverse protein family bind other receptors, channels, or enzymes to form tightly regulated signaling modules, facilitating PKA interactions with its downstream effectors. In addition, these signaling modules often constitute feedback loops between kinases and phosphatases or recruit phosphodiesterases to terminate the cAMP signal (3).Our labs previously identified a complex containing AKAP79/ 150 and type 5 adenylyl cyclase (AC), that facilitates the spatiotemporal organization of cAMP signaling (4). AKAP79 inhibits AC5 activity, while providing a mechanism for feedback inhibition via PKA phosphorylation of anchored AC5. However, with Ϸ30 gene families of AKAPs identified thus far, and nine mammalian isoforms of AC, it begs the question, does AKAP scaffolding of AC and PKA represent a general paradigm for cAMP signaling? The AKAP Yotiao represents an ideal test case to begin to address this question. Yotiao is a splice variant of the AKAP9 gene and is present on the plasma membrane (5, 6). In addition to PKA, Yotiao binds protein phosphatase 1 (PP1), NMDA receptors, the heart potassium channel subunit KCNQ1, and the IP 3 R1 (5, 7-9). Interestingly, AKAP anchored PKA phosphorylation of the NMDA receptor, KCNQ1, and IP 3 R1 is necessary for each effector's normal function (8-11). For example, disruption of the KCNQ1 association with Yotiao gives rise to long QT syndrome, a type of heart arrhythmia that can be fatal (12). The requirement for a tight coupling between PKA and KCNQ1, and other effectors suggests that cAMP production must also be tightly regulated, perhaps as even part of this complex.We now show that Yotiao is associated with brain and heart adenylyl cyclases. Yotiao displays specificity am...

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Dynamic Regulation of cAMP Synthesis through Anchored PKA-Adenylyl Cyclase V/VI Complexes

Cited by 191 publications

References 31 publications

G protein-coupled Receptor 30 (GPR30) Forms a Plasma Membrane Complex with Membrane-associated Guanylate Kinases (MAGUKs) and Protein Kinase A-anchoring Protein 5 (AKAP5) That Constitutively Inhibits cAMP Production

G protein-coupled Receptor 30 (GPR30) Forms a Plasma Membrane Complex with Membrane-associated Guanylate Kinases (MAGUKs) and Protein Kinase A-anchoring Protein 5 (AKAP5) That Constitutively Inhibits cAMP Production

Role of AKAP79/150 Protein in β1-Adrenergic Receptor Trafficking and Signaling in Mammalian Cells

The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain

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