cAMP-Dependent Protein Kinase and cGMP-Dependent Protein Kinase as Cyclic Nucleotide Effectors

Lorenz, Robin; Bertinetti, Daniela

doi:10.1007/164_2015_36

Cited by 28 publications

(25 citation statements)

References 80 publications

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“…In addition, we found that several other SNF1‐subfamily protein kinases can also target the regulated phosphorylation sites in vitro (Figure 8). Consistent with the fourth possibility, cGMP‐activated kinases (Protein Kinase G) have been shown to be activated by high levels of cAMP, similar to those measured in PKA‐null cells in the present study 32,33 . Prior studies have found that AMPK can be activated by nitric oxide working through cGMP 34,35 pointing to a role for Protein Kinase G in the regulation of AMPK.…”

Section: Discussionsupporting

confidence: 89%

PKA‐independent vasopressin signaling in renal collecting duct

et al. 2020

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Vasopressin regulates renal water excretion by binding to a Gαs‐coupled receptor (V2R) in collecting duct cells, resulting in increased water permeability through regulation of the aquaporin‐2 (AQP2) water channel. This action is widely accepted to be associated with cAMP‐mediated activation of protein kinase A (PKA). Here, we use phosphoproteomics in collecting duct cells in which PKA has been deleted (CRISPR‐Cas9) to identify PKA‐independent responses to vasopressin. The results show that V2R‐mediated vasopressin signaling is predominantly, but not entirely, PKA‐dependent. Upregulated sites in PKA‐null cells include Ser256 of AQP2, which is critical to regulation of AQP2 trafficking. In addition, phosphorylation changes in the protein kinases Stk39 (SPAK) and Prkci (an atypical PKC) are consistent with PKA‐independent regulation of these protein kinases. Target motif analysis of the phosphopeptides increased in PKA‐null cells indicates that vasopressin activates one or more members of the AMPK/SNF1‐subfamily of basophilic protein kinases. In vitro phosphorylation assays using recombinant, purified SNF1‐subfamily kinases confirmed postulated target specificities. Of interest, measured IBMX‐dependent cAMP levels were an order of magnitude higher in PKA‐null than in PKA‐intact cells, indicative of a PKA‐dependent feedback mechanism. Overall, the findings support the conclusion that V2‐receptor mediated signaling in collecting duct cells is in part PKA‐independent.

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Section: Discussionsupporting

confidence: 89%

PKA‐independent vasopressin signaling in renal collecting duct

et al. 2020

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“…However, as cAMP binding to PKA RIα is highly cooperative, cyclic nucleotide binding to the full-length protein and the isolated CNB domains cannot be directly compared [43]. Previous studies on isolated CNB domains of PKA RIα showed that CNB-B is more selective for cAMP compared with CNB-A [41,44]. In agreement with former studies, the selectivity of the isolated CNB-B remains the same as for CNB-B in the full-length PKA RIα [42].…”

Section: Resultsmentioning

confidence: 99%

Mutations of PKA cyclic nucleotide-binding domains reveal novel aspects of cyclic nucleotide selectivity

Lorenz

Moon

Kim

et al. 2017

Biochemical Journal

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Cyclic AMP and cyclic GMP are ubiquitous second messengers that regulate the activity of effector proteins in all forms of life. The main effector proteins, the 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) and the 3′,5′-cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG), are preferentially activated by cAMP and cGMP, respectively. However, the molecular basis of this cyclic nucleotide selectivity is still not fully understood. Analysis of isolated cyclic nucleotide-binding (CNB) domains of PKA regulatory subunit type Iα (RIα) reveals that the C-terminal CNB-B has a higher cAMP affinity and selectivity than the N-terminal CNB-A. Here, we show that introducing cGMP-specific residues using site-directed mutagenesis reduces the selectivity of CNB-B, while the combination of two mutations (G316R/A336T) results in a cGMP-selective binding domain. Furthermore, introducing the corresponding mutations (T192R/A212T) into the PKA RIα CNB-A turns this domain into a highly cGMP-selective domain, underlining the importance of these contacts for achieving cGMP specificity. Binding data with the generic purine nucleotide 3′,5′-cyclic inosine monophosphate (cIMP) reveal that introduced arginine residues interact with the position 6 oxygen of the nucleobase. Co-crystal structures of an isolated CNB-B G316R/A336T double mutant with either cAMP or cGMP reveal that the introduced threonine and arginine residues maintain their conserved contacts as seen in PKG I CNB-B. These results improve our understanding of cyclic nucleotide binding and the molecular basis of cyclic nucleotide specificity.

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“…Three PKG isoforms have been identified (PKG-type Iα (PKG Iα), PKG-type Iβ (PKG Iβ), and PKG-type II (PKG II)), whereby PKG Iα and PKG Iβ are splice variants originating from alternative splicing of one single gene. In the cardiovascular system, PKG I is the major isoform—PKG Iα and PKG Iβ are expressed in VSMCs—while ECs express PKG Iβ, and CMs express PKG Iα [ 1 , 26 , 46 , 47 , 48 , 49 , 50 ]. Second, cyclic nucleotide-gated (CNG) channels, nonselective cation channels, can be activated by the binding of cGMP or cyclic adenosine 3′,5′-monophosphate (cAMP).…”

Section: Cgmp Signaling In the Cardiovascular Systemmentioning

confidence: 99%

cGMP Signaling in the Cardiovascular System—The Role of Compartmentation and Its Live Cell Imaging

Bork

Nikolaev

2018

IJMS

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The ubiquitous second messenger 3′,5′-cyclic guanosine monophosphate (cGMP) regulates multiple physiologic processes in the cardiovascular system. Its intracellular effects are mediated by stringently controlled subcellular microdomains. In this review, we will illustrate the current techniques available for real-time cGMP measurements with a specific focus on live cell imaging methods. We will also discuss currently accepted and emerging mechanisms of cGMP compartmentation in the cardiovascular system.

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cAMP-Dependent Protein Kinase and cGMP-Dependent Protein Kinase as Cyclic Nucleotide Effectors

Cited by 28 publications

References 80 publications

PKA‐independent vasopressin signaling in renal collecting duct

PKA‐independent vasopressin signaling in renal collecting duct

Mutations of PKA cyclic nucleotide-binding domains reveal novel aspects of cyclic nucleotide selectivity

cGMP Signaling in the Cardiovascular System—The Role of Compartmentation and Its Live Cell Imaging

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