Impaired relaxation of stomach smooth muscle in mice lacking cyclic GMP‐dependent protein kinase I

Ny, Lars; Pfeifer, Alexander; Aszódi, Attila; Ahmad, Marianne; Alm, Per; Hedlund, Petter; Fässler, Reinhard; Andersson, Karl‐Erik

doi:10.1038/sj.bjp.0703061

Cited by 54 publications

(51 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…10 PRKG1 knockout mice have a decreased lifespan, defects in relaxation of vascular, visceral, and penile smooth muscle, disturbed platelet adhesion and activation, and impaired guidance of sensory axons during embryogenesis. 11,12 The NO/cGMP pathway, where PRKG1 is one of the downstream players, mediates regulatory effects on key enzymes of fatty acid synthesis and oxidation and may be involved in physiological control of fatty acid metabolism in liver. 13 Leptin-deficient obese mice show significant changes in NO/cGMP signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Lack of association between polymorphism of the human cyclic GMP-dependent protein kinase gene and obesity

et al. 2005

View full text Add to dashboard Cite

OBJECTIVE:To investigate whether genetic variation in the cyclic GMP-dependent protein kinase gene (PRKG1) is associated with obesity. METHODS: The study included 143 individuals from New York City area, NY, USA. The subjects were sampled on the basis of body mass index (BMI): obese (BMI ranging from 33.8 to 89.5 kg/m 2 ), and nonobese (BMI ranging from 16.0 to 29.4 kg/m 2 ). The association between C2276T polymorphism in PRKG1 gene and obesity was tested using linear regression analysis. RESULTS: BMI levels were predicted by linear regression models adjusted for demographic factors. An analysis was performed twice: in individuals of all ethnical backgrounds and in European-Americans only. In both cases, genotype did not have a significant effect. CONCLUSION: We found no evidence that the C2276T polymorphism in the PKRG1 gene is associated with obesity.

show abstract

Section: Discussionmentioning

confidence: 99%

Lack of association between polymorphism of the human cyclic GMP-dependent protein kinase gene and obesity

et al. 2005

View full text Add to dashboard Cite

show abstract

“…62,127,[191][192][193][194][195][196][197] Numerous studies have shown responses to NO in the GI tract depend upon the production of cyclic GMP (cGMP) by soluble guanylate cyclase. [198][199][200] Guanylate cyclase is a heterodimer comprised of 2 subunits, α and β. Using immunohistochemistry Iino et al 182,201 showed that both subunits are strongly expressed in ICC but not resolved in smooth muscle.…”

Section: Functional Evidence Demonstrating the Importance Of Interstimentioning

confidence: 99%

“…NO elicits hyperpolarization and relaxation responses in GI muscles, and these responses depend upon generation of cGMP and cGMP dependent protein kinase. 199,200,220 The proteins that mediate membrane hyperpolarization are debated, and some investigators have viewed the hyperpolarization response to be due to activation of a K + conductance [231][232][233] while others have suggested the response is due to suppression of an inward current due either to a non-selective cation conductance 206 or a chloride conductance. 234 Resolution of these questions and determining which of the cells in the SIP syncytium express the specific types of ion channels responsible for responses to NO will require additional experimentation.…”

Section: Evidence Opposing a Role For Interstitial Cells Of Cajal In mentioning

confidence: 99%

See 1 more Smart Citation

The Significance of Interstitial Cells in Neurogastroenterology

Blair¹,

Rhee²,

Sanders³

et al. 2014

J Neurogastroenterol Motil

116

111

View full text Add to dashboard Cite

Smooth muscle layers of the gastrointestinal tract consist of a heterogeneous population of cells that include enteric neurons, several classes of interstitial cells of mesenchymal origin, a variety of immune cells and smooth muscle cells (SMCs). Over the last number of years the complexity of the interactions between these cell types has begun to emerge. For example, interstitial cells, consisting of both interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor alpha-positive (PDGFRα + ) cells generate pacemaker activity throughout the gastrointestinal (GI) tract and also transduce enteric motor nerve signals and mechanosensitivity to adjacent SMCs. ICC and PDGFRα + cells are electrically coupled to SMCs possibly via gap junctions forming a multicellular functional syncytium termed the SIP syncytium. Cells that make up the SIP syncytium are highly specialized containing unique receptors, ion channels and intracellular signaling pathways that regulate the excitability of GI muscles. The unique role of these cells in coordinating GI motility is evident by the altered motility patterns in animal models where interstitial cell networks are disrupted. Although considerable advances have been made in recent years on our understanding of the roles of these cells within the SIP syncytium, the full physiological functions of these cells and the consequences of their disruption in GI muscles have not been clearly defined. This review gives a synopsis of the history of interstitial cell discovery and highlights recent advances in structural, molecular expression and functional roles of these cells in the GI tract.

show abstract

“…They target different components of the contractile signaling pathways that attenuate MLCK activity and/or augment MLC phosphatase (MLCP) activity, which eventually induce dephosphorylation of MLC 20 and thus smooth muscle relaxation (7,30,32,43). Although generation of both nucleotides and activation of both kinases are the physiological norm, dysfunctions of gastrointestinal motility in vivo and nitrergic relaxation in vitro in mice lacking neuronal NO synthase (nNOS), soluble guanylyl cyclase (sGC), or PKG-I suggest an important role for cGMP signaling in smooth muscle relaxation (5,11,27,35).The levels of cAMP and cGMP in gastrointestinal smooth muscle depend on the rates of their synthesis by cyclases and degradation by phosphodiesterases (PDEs) (3,8,10,29,40). cAMP is rapidly degraded by the cAMP-preferring PDE3 and cAMP-specific PDE4 (10, 33).…”

mentioning

confidence: 99%

Differential expression of multidrug resistance protein 5 and phosphodiesterase 5 and regulation of cGMP levels in phasic and tonic smooth muscle

Al‐Shboul

Mahavadi

Sriwai

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Al-Shboul O, Mahavadi S, Sriwai W, Grider JR, Murthy KS. Differential expression of multidrug resistance protein 5 and phosphodiesterase 5 and regulation of cGMP levels in phasic and tonic smooth muscle. Am J Physiol Gastrointest Liver Physiol 305: G314-G324, 2013. First published June 13, 2013; doi:10.1152/ajpgi.00457.2012.-Previous studies have identified differences in the expression of proteins that regulate myosin light chain phosphorylation and contraction in tonic and phasic smooth muscle. cGMP plays a critical role in smooth muscle relaxation and is important for optimal function of phasic and tonic smooth muscle. The intracellular cGMP levels are regulated by its hydrolysis via phosphodiesterase 5 (PDE5) and efflux via novel multidrug resistance protein 5 (MRP5). In the present study we tested the hypothesis that the differences in the phasic and tonic behavior of smooth muscles may be related to differences in mechanisms that terminate cGMP signaling. Expression of PDE5 and MRP5 was significantly (more than 2-fold) higher in fundus compared with antrum. The NO donor S-nitrosoglutathione (GSNO) caused an increase in PDE5 activity and intra-and extracellular cGMP levels in both fundus and antrum. Stimulation of PDE5 activity and increase in extracellular cGMP were significantly higher in fundus, whereas increase in intracellular cGMP was significantly higher in antrum. GSNO-induced increase in extracellular cGMP was blocked in dispersed cells by the cyclic nucleotide export blocker probenecid and in cultured muscle cells by depletion of ATP or suppression of MRP5 by siRNA, providing evidence that cGMP efflux was mediated by ATPdependent export via MRP5. Consistent with the higher expression and activity levels of PDE5 and MRP5, GSNO-induced PKG activity and muscle relaxation were significantly lower in muscle cells from fundus compared with antrum. Thus higher expression of PDE5 and MRP5 in muscle cells from fundus correlates with tonic phenotype of muscle. cyclic nucleotides; MRP5; phasic muscle; tonic muscle GASTROINTESTINAL TRACT smooth muscle possesses distinct regional and functional properties that distinguish it from other types of visceral and vascular smooth muscle. An essential step in smooth muscle contraction is phosphorylation of the 20-kDa regulatory myosin light chain (MLC 20 ) by a Ca 2ϩ /calmodulindependent or -independent myosin light chain (MLC) kinase (MLCK) that transfers the phosphate group from ATP to Ser 19 (16,20,30,43,45,46). Smooth muscle relaxation is initiated by targeting MLC 20 dephosphorylation (43). Most agents cause relaxation by stimulating the production of cAMP (e.g., vasoactive intestinal peptide and its homologue pituitary adenylate cyclase-activating peptide) or cGMP [e.g., nitric oxide (NO)] leading to activation of PKA, PKG, or both (25,26,30,43). cAMP-activated PKA and cGMP-activated PKG are the main enzymes that induce relaxation in smooth muscle. They target different components of the contractile signaling pathways that attenuate MLCK activity and/or augment ...

show abstract

Impaired relaxation of stomach smooth muscle in mice lacking cyclic GMP‐dependent protein kinase I

Cited by 54 publications

References 26 publications

Lack of association between polymorphism of the human cyclic GMP-dependent protein kinase gene and obesity

Lack of association between polymorphism of the human cyclic GMP-dependent protein kinase gene and obesity

The Significance of Interstitial Cells in Neurogastroenterology

Differential expression of multidrug resistance protein 5 and phosphodiesterase 5 and regulation of cGMP levels in phasic and tonic smooth muscle

Contact Info

Product

Resources

About