Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: PRKG1
Cytogenetic location: 10q11.23-q21.1 Genomic coordinates (GRCh38): 10:50,990,888-52,298,350 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q11.23-q21.1 | Aortic aneurysm, familial thoracic 8 | 615436 | Autosomal dominant | 3 |
Cyclic GMP and cyclic GMP-dependent protein kinase play important roles in physiologic processes such as relaxation of vascular smooth muscle and inhibition of platelet aggregation. Two main forms of cGK have been identified: a soluble form designated type I and an intrinsic membrane-bound form designated type II. Sandberg et al. (1989) isolated and characterized cDNA clones for the type I beta isozyme from human placenta libraries.
Tamura et al. (1996) cloned a human cGKI-alpha cDNA by RT-PCR of aorta RNA using primers based on the sequence of a bovine cGKI-alpha cDNA. The predicted 671-amino acid human cGKI-alpha protein is nearly identical to bovine cGKI-alpha. Based on Southern blot and sequence analyses, Tamura et al. (1996) suggested that cGKI-alpha and cGKI-beta are generated by alternative splicing of a single gene. By Northern blot analysis, cGKI-alpha was abundantly expressed as a 7.0-kb mRNA in aorta, heart, kidneys and adrenals; the 7.0-kb cGKI-beta mRNA was abundantly expressed only in the uterus.
Orstavik et al. (1997) noted that type I cGK is a homodimer, with each monomer containing a regulatory cGMP-binding domain and a catalytic domain. By Northern blot analysis, they showed that type I cGK-alpha mRNA was most abundant in lung and placenta, while type I cGK-beta was expressed at highest levels in bladder, uterus, adrenal gland, and fallopian tube.
Orstavik et al. (1997) reported that the type I cGK gene contains 19 exons spanning at least 220 kb. The first 2 exons, which the authors called 1-alpha and 1-beta, are used alternatively and encode the alpha isoform- and beta isoform-specific sequences. Orstavik et al. (1997) noted that 5 of the 7 splice sites in the Drosophila melanogaster DG2 gene, which encodes a cGK, are also present in the human type I cGK gene. They reported that levels of the DG2-encoded cGK in Drosophila affect food-search behavior and account for a naturally occurring behavioral polymorphism.
By Southern blots of human/hamster somatic cell hybrids, Orstavik et al. (1992) localized the PRKGR1B gene to chromosome 10. The gene was regionally localized to 10q11.2 by in situ hybridization.
By yeast 2-hybrid analysis and immunoprecipitation of mouse testis, Yuasa et al. (2000) showed that mouse Gkap42 (GKAP1; 611356) interacted with cGKI-alpha. Gcap42 was phosphorylated by cGKI-alpha in intact cells. A kinase-deficient mutant of cGKI-alpha stably associated with Gkap42, and binding of cGMP to cGKI-alpha facilitated their release from Gkap42. Yuasa et al. (2000) concluded that Gkap42 may function as an anchoring protein for cGKI-alpha and that cGKI-alpha may participate in germ cell development through phosphorylation of Golgi-associated proteins, such as GKAP42.
Li et al. (2003) showed that PRKG1 plays an important stimulatory role in platelet activation. Expression of recombinant PRKG1 in a reconstituted cell model enhanced von Willebrand factor (VWF; 613160)-induced activation of the platelet integrin alpha-IIb (607759)/beta-3 (173470). Prkg1 knockout mice showed impaired platelet responses to VWF or low doses of thrombin and prolonged bleeding time. Human platelet aggregation induced by VWF or low-dose thrombin was inhibited by PRKG1 inhibitors but enhanced by cGMP. Furthermore, a cGMP-enhancing agent, sildenafil, promoted VWF- or thrombin-induced platelet aggregation. The cGMP-stimulated platelet responses were biphasic, consisting of an initial transient stimulatory response that promoted platelet aggregation and a subsequent inhibitory response that limited the size of thrombi.
Burgoyne et al. (2007) found that the cGMP-dependent protein kinase PKG functions directly as a redox sensor. The I-alpha isoform, PKGI-alpha, formed an interprotein disulfide linking its 2 subunits in cells exposed to exogenous hydrogen peroxide. This oxidation directly activated the kinase in vitro, and in rat cells and tissues. The affinity of the kinase for substrates it phosphorylates was enhanced by disulfide formation. This oxidation-induced activation represents an alternate mechanism for regulation along with the classic activation involving nitric oxide and cGMP. Burgoyne et al. (2007) concluded that this mechanism underlies cGMP-independent vasorelaxation in response to oxidants in the cardiovascular system and provides a molecular explanation for how hydrogen peroxide can operate as an endothelium-derived hyperpolarizing factor.
Ranek et al. (2019) showed that in the heart, or in isolated cardiomyocytes or fibroblasts, PKG1 phosphorylates 2 adjacent serine residues in TSC2 (191092) (S1365 and S1366 in mice; S1364 and S1365 in humans), which could bidirectionally control mTORC1 (see 601231) activity stimulated by growth factors or hemodynamic stress, and consequently modulate cell growth and autophagy. However, basal mTORC1 activity remained unchanged. PKG1 is a primary effector of nitric oxide and natriuretic peptide (see 108780) signaling, and protects against heart disease. Suppression of hypertrophy and stimulation of autophagy in cardiomyocytes by PKG1 requires TSC2 phosphorylation. Homozygous knockin mice that expressed a phosphorylation-silencing mutation in TSC2 (S1365A) developed worse heart disease and had higher mortality after sustained pressure overload of the heart, owing to mTORC1 hyperactivity that could not be rescued by PKG1 stimulation. However, cardiac disease was reduced, and survival of heterozygote Tsc2(S1365A) knockin mice subjected to the same stress was improved by PKG1 activation or expression of a phosphorylation-mimicking mutation (Tsc2(S1365E)). Resting mTORC1 activity was not altered in either knockin model. Ranek et al. (2019) concluded that TSC2 phosphorylation is both required and sufficient for PKG1-mediated cardiac protection against pressure overload. They suggested that the serine residues identified by them provided a genetic tool for bidirectional regulation of the amplitude of stress-stimulated mTORC1 activity.
In 4 unrelated families with autosomal dominant thoracic aortic aneurysm and dissection (AAT8; 615436), Guo et al. (2013) identified heterozygosity for a missense mutation in the PRKG1 gene (R177Q; 176894.0001) that segregated with disease in each family and was not found in controls. Although the mutation disrupts binding to the high-affinity cGMP binding site within the regulatory domain, R177Q mutant PRKG1 is constitutively active even in the absence of cGMP, resulting in decreased phosphorylation of the myosin regulatory light chain in fibroblasts that is predicted to cause decreased contraction of vascular smooth muscle cells.
Pfeifer et al. (1998) generated mice deficient in cGKI by targeted disruption. Loss of cGKI abolished nitric oxide/cGMP-dependent relaxation of smooth muscle, resulting in severe vascular and intestinal dysfunction. However, cGKI-deficient smooth muscle responded normally to cAMP, indicating that cAMP and cGMP signal via independent pathways, with cGKI being the specific mediator of the nitric oxide/cGMP effects in murine smooth muscle.
Foller et al. (2008) found that cGKI deficiency in mice resulted in anemia and splenomegaly. Compared with control mice, cGKI mutants had significantly lower red blood cell count, packed cell volume, and hemoglobin concentration. Anemia was associated with higher reticulocyte number and an increase in plasma erythropoietin (133170) concentration. Compared with control erythrocytes, cGKI-deficient erythrocytes exhibited in vitro a higher cytosolic Ca(2+) concentration and increased phosphatidylserine exposure, which was paralleled by faster erythrocyte clearance in vivo. Foller et al. (2008) concluded that cGKI is a mediator of erythrocyte survival.
Jaumann et al. (2012) found that Prkg1-null mice had a normal hearing threshold, but they were more vulnerable than wildtype mice to noise-induced hearing loss and showed markedly less recovery than wildtype mice following acoustic trauma. Prkg1 was expressed in sensory cells and neurons of the inner ear of wildtype mice, and its expression partly overlapped that of cGMP-dependent phosphodiesterase Pde5 (PDE5A; 603310). Pharmacologic inhibition of Pde5 in wildtype mice and rats almost completely prevented noise-induced cochlear damage and caused Prkg1-dependent upregulation of poly(ADP-ribose) in hair cells and spiral ganglion. Jaumann et al. (2012) concluded that the protective effect of Prkg1 involves activation of poly(ADP-ribose) polymerase (see 173870).
In 4 unrelated families with autosomal dominant thoracic aortic aneurysm and dissection (AAT8; 615436), 1 of which had previously been described by Tran-Fadulu et al. (2006) (family TAA216), Guo et al. (2013) identified heterozygosity for a c.530G-A transition in exon 3 of the PRKG1 gene, resulting in an arg177-to-gln (R177Q) substitution at a highly conserved residue in the CNB-A domain. The mutation segregated with disease in each family and was not found in 8,600 European American or 4,400 African American chromosomes in the NHLBI Exome Sequencing Project Exome Variant Server. Haplotype analysis of SNPs flanking the PRKG1 gene showed that 2 of the families (TAA508 and TAA690) shared a common haplotype in this region, but the mutation-associated haplotype was different in the other 2 families. Functional analysis using a fluorescence polarization assay demonstrated that the mutant results in a CNB-A domain that does not bind or respond to cGMP; however, transfection studies in HEK293T cells showed that the mutant was highly active in phosphotransferase activity even without cGMP, whereas wildtype protein required cGMP for activation. Patient fibroblasts showed decreased levels of phosphorylated regulatory light chain compared to controls.
Burgoyne, J. R., Madhani, M., Cuello, F., Charles, R. L., Brennan, J. P., Schroder, E., Browning, D. D., Eaton, P. Cysteine redox sensor in PKGI-alpha enables oxidant-induced activation. Science 317: 1393-1397, 2007. [PubMed: 17717153] [Full Text: https://doi.org/10.1126/science.1144318]
Foller, M., Feil, S., Ghoreschi, K., Koka, S., Gerling, A., Thunemann, M., Hofmann, F., Schuler, B., Vogel, J., Pichler, B., Kasinathan, R. S., Nicolay, J. P., Huber, S. M., Lang, F., Feil, R. Anemia and splenomegaly in cGKI-deficient mice. Proc. Nat. Acad. Sci. 105: 6771-6776, 2008. [PubMed: 18443297] [Full Text: https://doi.org/10.1073/pnas.0708940105]
Guo, D., Regalado, E., Casteel, D. E., Santos-Cortez, R. L., Gong, L., Kim, J. J., Dyack, S., Horne, S. G., Chang, G., Jondeau, G., Boileau, C., Coselli, J. S., and 10 others. Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am. J. Hum. Genet. 93: 398-404, 2013. [PubMed: 23910461] [Full Text: https://doi.org/10.1016/j.ajhg.2013.06.019]
Jaumann, M., Dettling, J., Gubelt, M., Zimmermann, U., Gerling, A., Paquet-Durand, F., Feil, S., Wolpert, S., Franz, C., Varakina, K., Xiong, H., Brandt, N., and 11 others. cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function. Nature Med. 18: 252-259, 2012. [PubMed: 22270721] [Full Text: https://doi.org/10.1038/nm.2634]
Li, Z., Xi, X., Gu, M., Feil, R., Ye, R. D., Eigenthaler, M., Hofmann, F., Du, X. A stimulatory role for cGMP-dependent protein kinase in platelet activation. Cell 112: 77-86, 2003. [PubMed: 12526795] [Full Text: https://doi.org/10.1016/s0092-8674(02)01254-0]
Orstavik, S., Natarajan, V., Tasken, K., Jahnsen, T., Sandberg, M. Characterization of the human gene encoding the type I-alpha and type I-beta cGMP-dependent protein kinase (PRKG1). Genomics 42: 311-318, 1997. [PubMed: 9192852] [Full Text: https://doi.org/10.1006/geno.1997.4743]
Orstavik, S., Sandberg, M., Berube, D., Natarajan, V., Simard, J., Walter, U., Gagne, R., Hansson, V., Jahnsen, T. Localization of the human gene for type I cyclic GMP-dependent protein kinase to chromosome 10. Cytogenet. Cell Genet. 59: 270-273, 1992. [PubMed: 1544322] [Full Text: https://doi.org/10.1159/000133267]
Osborne, K. A, Robichon, A., Burgess, E., Butland, S., Shaw, R. A., Coulthard, A., Pereira, H. S., Greenspan, R. J., Sokolowski, M. B. Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila. Science 277: 834-836, 1997. [PubMed: 9242616] [Full Text: https://doi.org/10.1126/science.277.5327.834]
Pfeifer, A., Klatt, P., Massberg, S., Ny, L., Sausbier, M., Hirneill, C., Wang, G.-X., Korth, M., Aszodi, A., Andersson, K.-E., Krombach, F., Mayerhofer, A., Ruth, P., Fassler, R., Hofmann, F. Defective smooth muscle regulation in cGMP kinase I-deficient mice. EMBO J. 17: 3045-3051, 1998. [PubMed: 9606187] [Full Text: https://doi.org/10.1093/emboj/17.11.3045]
Ranek, M. J., Kokkonen-Simon, K. M., Chen, A., Dunkerly-Eyring, B. L., Vera, M. P., Oeing, C. U., Patel, C. H., Nakamura, T., Zhu, G., Bedja, D., Sasaki, M., Holewinski, R. J., Van Eyk, J. E., Powell, J. D., Lee, D. I., Kass, D. A. PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress. Nature 566: 264-269, 2019. [PubMed: 30700906] [Full Text: https://doi.org/10.1038/s41586-019-0895-y]
Sandberg, M., Natarajan, V., Ronander, I., Kalderon, D., Walter, U., Lohmann, S. M., Jahnsen, T. Molecular cloning and predicted full-length amino acid sequence of the type I beta isozyme of cGMP-dependent protein kinase from human placenta: tissue distribution and developmental changes in rat. FEBS Lett. 255: 321-329, 1989. [PubMed: 2792381] [Full Text: https://doi.org/10.1016/0014-5793(89)81114-7]
Tamura, N., Itoh, H., Ogawa, Y., Nakagawa, O., Harada, M., Chun, T.-H., Suga, S., Yoshimasa, T., Nakao, K. cDNA cloning and gene expression of human type I-alpha cGMP-dependent protein kinase. Hypertension 27: 552-557, 1996. [PubMed: 8613202] [Full Text: https://doi.org/10.1161/01.hyp.27.3.552]
Tran-Fadulu, V., Chen, J. H., Lemuth, D., Neichoy, B. T., Yuan, J., Gomes, N., Sparks, E., Kramer, L. A., Guo, D., Pannu, H., Braverman, A. C., Shete, S., Milewicz, D. M. Familial thoracic aortic aneurysms and dissections: three families with early-onset ascending and descending aortic dissections in women. Am. J. Med. Genet. 140A: 1196-1202, 2006. Note: Erratum: Am. J. Med. Genet. 140A: 1796 only, 2006. [PubMed: 16646045] [Full Text: https://doi.org/10.1002/ajmg.a.31236]
Yuasa, K., Omori, K., Yanaka, N. Binding and phosphorylation of a novel male germ cell-specific cGMP-dependent protein kinase-anchoring protein by cGMP-dependent protein kinase I-alpha. J. Biol. Chem. 275: 4897-4905, 2000. [PubMed: 10671526] [Full Text: https://doi.org/10.1074/jbc.275.7.4897]