cGMP Regulated Protein Kinases (cGK)

Hofmann, Franz; Bernhard, Detlef; Łukowski, Robert; Weinmeister, Pascal

doi:10.1007/978-3-540-68964-5_8

Cited by 170 publications

(183 citation statements)

References 173 publications

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“…By binding to PKG, cGMP regulates intracellular signaling pathways that control a wide range of intracellular processes, such as cell differentiation, platelet activation, memory formation, and vasodilation (1)(2)(3)(4)(5). The PKG signaling pathways are often distinct from those regulated by cAMP-dependent proteins such as protein kinase A (PKA) (6 -12).…”

mentioning

confidence: 99%

Mechanism of cAMP Partial Agonism in Protein Kinase G (PKG)

VanSchouwen¹,

Selvaratnam²,

Giri³

et al. 2015

Journal of Biological Chemistry

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Background: Protein kinase G (PKG) is selectively activated by cGMP, but the mechanism of cGMP-versus-cAMP selectivity is not fully understood. Results: cAMP-bound PKG exists in a dynamic exchange between three states, inactive, active, and a partially autoinhibited state, which results in partial agonism. Conclusion: Partial agonism contributes to cGMP-versus-cAMP selectivity. Significance: The cGMP-versus-cAMP selectivity controls the cross-talk between cGMP-and cAMP-dependent signaling pathways.

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mentioning

confidence: 99%

Mechanism of cAMP Partial Agonism in Protein Kinase G (PKG)

VanSchouwen¹,

Selvaratnam²,

Giri³

et al. 2015

Journal of Biological Chemistry

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“…As the main effector of the nitric oxide/cGMP signaling cascade, cGMP-dependent protein kinase (PKG) regulates smooth muscle tone, inhibits platelet activation, and modulates neuronal functions (1). In mammalian cells, two different genes encode a soluble type I PKG and a membrane-anchored type II PKG (1).…”

mentioning

confidence: 99%

A Crystal Structure of the Cyclic GMP-dependent Protein Kinase Iβ Dimerization/Docking Domain Reveals Molecular Details of Isoform-specific Anchoring*

Casteel

Smith-Nguyen

Sankaran

et al. 2010

Journal of Biological Chemistry

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Cyclic GMP-dependent protein kinase (PKG) is a key mediator of the nitric oxide/cGMP signaling pathway and plays a central role in regulating cardiovascular and neuronal functions. The N-terminal ϳ50 amino acids of the kinase are required for homodimerization and association with isoform-specific PKGanchoring proteins (GKAPs), which target the kinase to specific substrates. To understand the molecular details of PKG dimerization and gain insight into its association with GKAPs, we solved a crystal structure of the PKG I␤ dimerization/docking domain. Our structure provides molecular details of this unique leucine/isoleucine zipper, revealing specific hydrophobic and ionic interactions that mediate dimerization and demonstrating the topology of the GKAP interaction surface.As the main effector of the nitric oxide/cGMP signaling cascade, cGMP-dependent protein kinase (PKG) regulates smooth muscle tone, inhibits platelet activation, and modulates neuronal functions (1). In mammalian cells, two different genes encode a soluble type I PKG and a membrane-anchored type II PKG (1). Both enzymes form homodimers through an N-terminal leucine/isoleucine zipper domain. PKG I has two splice variants (␣ and ␤) that differ in the first ϳ100 amino acids, resulting in unique dimerization and autoinhibitory domains. The leucine/isoleucine zipper domain mediates interaction with isotype-specific G-kinase-anchoring proteins (GKAPs), 2 targeting PKG I␣ and I␤ to different subcellular compartments and intracellular substrates (2); therefore, we refer to this region as the dimerization and docking (D/D) domain. The domain organization of PKG is shown in Fig. 1. The N-terminal D/D domain is followed by an inhibitory sequence (IS), tandem cyclic nucleotide binding pockets, and the catalytic domain. The D/D domain contains a distinct primary sequence, with a repeating pattern of leucines and isoleucines every seven residues (Fig. 1). This pattern is referred to as a heptad repeat, and the positions of residues are labeled a-g.Specific binding partners for PKG I␣ include the myosin phosphatase targeting subunit (MYPT1) of myosin light chain phosphatase and the regulator of G-protein signaling-2 (RGS-2) (3, 4). Phosphorylation of MYPT1 by PKG I␣ activates its phosphatase activity, leading to dephosphorylation of myosin light chain, which desensitizes the contractile apparatus response to calcium, resulting in vasorelaxation (3). RGS-2 functions as a GTPase-activating protein for G␣ q subunits of heterotrimeric G-protein complexes, and phosphorylation of RGS-2 by PKG I␣ increases its activity toward G␣ q , uncoupling downstream signaling from G␣ qlinked receptors for vasoconstrictive agents (4). Specific binding partners for PKG I␤ include the inositol triphosphate receptor-associated PKG substrate (IRAG) and the transcriptional regulator TFII-I (5, 6). Phosphorylation of IRAG by PKG I␤ inhibits 1,4,5-inositol triphosphate receptordependent calcium release from the endoplasmic reticulum, contributing to smooth muscle relaxation (7). Phosphor...

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“…The PRKG1 gene product, protein kinase G-1 (PKG-1), is a serine/threonine-specific protein kinase that is activated by cGMP. 13 PKG-1 regulates vascular smooth muscle relaxation and modulates the contractility, growth, and apoptosis of cardiomyocytes. [1][2][3]13 In isolated myocytes from wild-type and cardiac-specific PKG-1 knockout mice, 2 the cGMP-PKG-1 signaling mediated a negative inotropic effect.…”

Section: Discussionmentioning

confidence: 99%

“…13 PKG-1 regulates vascular smooth muscle relaxation and modulates the contractility, growth, and apoptosis of cardiomyocytes. [1][2][3]13 In isolated myocytes from wild-type and cardiac-specific PKG-1 knockout mice, 2 the cGMP-PKG-1 signaling mediated a negative inotropic effect. In this study, the cGMP analogues (8-Br-cGMP and 8-pCPT-cGMP) reduced the cardiomyocyte force of contraction by ≈30% in electrically driven heart muscle from wild-type but not from PKG-1 knockout mice.…”

Section: Discussionmentioning

confidence: 99%

Left Ventricular Radial Function Associated With Genetic Variation in the cGMP-Dependent Protein Kinase

et al. 2013

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C yclic guanosine monophosphate (cGMP), an intracellular second messenger, exerts its action by cGMP-dependent protein kinases (PKG-1) and cGMP-regulated phoshodiesterases. In the cardiovascular system, cGMP signaling is an important regulator of endothelial cell, vascular smooth muscle, and cardiomyocyte function.1 Studies of isolated myocytes from wild-type and cardiac-specific PKG-1 knockout mice 2 demonstrated that cGMP-PKG-1 signaling mediates a negative inotropic effect. Furthermore, in cardiac myocytes, adenoviral expression of PKG-1 attenuated hypertrophy via inhibition of calcineurine-nuclear factor of activated T-cells signaling.3 A recent genome-wide association study 4 found that the common genetic variants (tag) in human PKG-1 gene (PRKG1) were significantly associated with changes in diastolic blood pressure in response to an acute salt load in 478 never-treated patients with hypertension.Taken together, the above observations raise the possibility that genetic variability in PRKG1 might affect left ventricular (LV) function and structure. In the Flemish Study on Environment, Genes, and Health Outcomes (FLEMENGHO), we therefore investigated whether LV function and structure were associated with tag PRKG1 polymorphisms. In this study, we assessed LV phenotypes by using classical M-mode and 2-dimensional echocardiography as well as tissue Doppler imaging, which is a sensitive technique to detect early stages of LV dysfunction. 5,6 Methods Study ParticipantsThe Ethics Committee of the University of Leuven approved the FLEMENGHO study. As described in detail in previous publications, 7,8 from August 1985 to December 2005, we recruited a random sample of families from a geographically defined area in northern Belgium. From May 2005 to April 2009, we reinvited 942 participants for a follow-up examination, including echocardiography, at our field center. We obtained informed written consent from 752 subjects (participation rate, 79.5%).From the current analysis, we excluded 67 subjects because of LV remodeling attributable to myocardial infarction or coronary revascularization (n=24), the presence of moderate or severe Abstract-cGMP-dependent protein kinase type I is a major mediator of cGMP signaling in the cardiovascular system.Recent studies on cardiac-specific PRKG1 knockout mice demonstrated that cGMP-dependent protein kinase type I mediates the negative inotropic effect of cGMP in the myocardium. We therefore investigated the association between left ventricular (LV) function and common polymorphisms in the PRKG1 gene in a general population. In 609 randomly selected participants (51.2% women; mean age, 48.8 years; 36.6% hypertensive) who were free from overt cardiac disease, we performed echocardiography and genotyped intronic tag single-nucleotide polymorphisms (SNPs) rs1904694, rs7897633, and rs7905063 in PRKG1. On the basis of color Doppler myocardial motion data, we calculated end-systolic longitudinal and radial deformation (strain) of the LV inferolateral wall. In multivariable-adjusted analy...

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cGMP Regulated Protein Kinases (cGK)

Cited by 170 publications

References 173 publications

Mechanism of cAMP Partial Agonism in Protein Kinase G (PKG)

Mechanism of cAMP Partial Agonism in Protein Kinase G (PKG)

A Crystal Structure of the Cyclic GMP-dependent Protein Kinase Iβ Dimerization/Docking Domain Reveals Molecular Details of Isoform-specific Anchoring*

Left Ventricular Radial Function Associated With Genetic Variation in the cGMP-Dependent Protein Kinase

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