scholarly journals Protein kinase G expression in the small intestine and functional importance for smooth muscle relaxation

1998 ◽  
Vol 275 (4) ◽  
pp. G629-G637 ◽  
Author(s):  
Andrea Huber ◽  
Peter Trudrung ◽  
Martin Storr ◽  
Hartmut Franck ◽  
Volker Schusdziarra ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Small Intestine ◽  
Protein Kinase ◽  
Muscle Relaxation ◽  
Inhibitory Effect ◽  
Enteric Neurons ◽  
Smooth Muscle Relaxation ◽  
No Donor ◽  
Cgmp Analog ◽  
Dependent Protein

In functional experiments, the nitric oxide (NO) donor N-morpholino- N-nitroso-aminoacetonitrile or the cGMP analog 8-(4-chlorophenylthio)-cGMP caused a concentration-dependent, tetrodotoxin-resistant relaxation of precontracted strips from rat small intestine. The inhibitory effect of both substances was completely blocked at lower concentrations and was significantly attenuated at higher concentrations by the selective cGMP-dependent protein kinase (cGK) antagonist KT-5823 (1 μM). cGK-I was identified by immunohistochemistry in circular and longitudinal muscle, lamina muscularis mucosae, and smooth muscle cells of the villi and in fibroblast-like cells of the small intestine. Additionally, there was staining of a subpopulation of myenteric and submucous plexus neurons. Double staining for neuronal NO synthase (nNOS) and cGK-I demonstrated a colocalization of these two enzymes. Western blot analysis of smooth muscle preparations and isolated nerve terminals demonstrated that these structures predominantly contain the cGK-Iβ isoenzyme, whereas the cGK-Iα expression is about threefold less. The isoform cGK-II was entirely confined to mucosal epithelial cells. These results show that cGK-I is expressed in different muscular structures of the small intestine and participates in the NO-induced relaxation of gastrointestinal smooth muscle. The presence of cGK-I in NOS-positive enteric neurons further suggests a possible neuronal action site.

Cyclic GMP-Dependent Protein Kinase and Smooth Muscle Relaxation

1992 ◽  
Vol 20 ◽  
pp. S18-S22
Author(s):  
Wolfgang Landgraf ◽  
Peter Ruth ◽  
Alexandra Keilbach ◽  
Boris May ◽  
Andrea Welling ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Cyclic Gmp ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Dependent Protein Kinase ◽  
Dependent Protein

Cyclic GMP-Dependent Protein Kinase and Smooth Muscle Relaxation

1992 ◽  
Vol 20 ◽  
pp. S18-S22 ◽  
Author(s):  
Wolfgang Landgraf ◽  
Peter Ruth ◽  
Alexandra Keilbach ◽  
Boris May ◽  
Andrea Welling ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Cyclic Gmp ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Dependent Protein Kinase ◽  
Dependent Protein

Endothelin-1-induced vasoconstriction is inhibited during erection in rats

2001 ◽  
Vol 281 (2) ◽  
pp. R476-R483 ◽  
Author(s):  
T. M. Mills ◽  
D. M. Pollock ◽  
R. W. Lewis ◽  
H. S. Branam ◽  
C. J. Wingard
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Muscle Relaxation ◽  
Corpus Cavernosum ◽  
Smooth Muscle Relaxation ◽  
No Donor ◽  
Intracavernosal Injection ◽  
Endothelin 1

Recent evidence indicates that endothelin-1 (ET-1) might be a principal vasoconstrictor in the penis. We report that ET-1 injection into the cavernous sinuses before erection sharply reduced the magnitude of subsequent erections. Corpus cavernosum pressure-to-mean arterial pressure ratios (CCP/MAP), with maximal ganglionic stimulation, were 0.62 ± 0.05 before ET-1 injection and 0.31 ± 0.05 after, indicating that ET-1 acted as a vasoconstrictor. When ET-1 was injected during a maximal neurally induced erection, the ability of ET-1 to attenuate subsequent erections was diminished (CCP/MAP 0.75 ± 0.02 before ET-1, 0.61 ± 0.03 after). At submaximal stimulation voltages, injection of ET-1 during erection also attenuated its vasoconstrictive effect. Similarly, when ET-1 was injected during erection induced by intracavernosal injection of the nitric oxide (NO) donor NOR-1, subsequent erections were not significantly suppressed (CCP/MAP 0.53 ± 0.04 before ET-1, 0.45 ± 0.04 after). These findings that ET-1-induced vasoconstriction is attenuated during erection are consistent with the hypothesis that NO mediates erection both by initiating pathways that cause smooth muscle relaxation and by inhibiting the vasoconstrictive actions of ET-1.

Roles of CaM kinase II and phospholamban in SNP-induced relaxation of murine gastric fundus smooth muscles

2006 ◽  
Vol 291 (2) ◽  
pp. C337-C347 ◽  
Author(s):  
Minkyung Kim ◽  
In Soo Han ◽  
Sang Don Koh ◽  
Brian A. Perrino
Keyword(s):  
Smooth Muscle ◽  
Soluble Guanylate Cyclase ◽  
Muscle Relaxation ◽  
Smooth Muscles ◽  
Cyclopiazonic Acid ◽  
Gastric Fundus ◽  
Smooth Muscle Relaxation ◽  
Cam Kinase Ii ◽  
Cam Kinase ◽  
No Donor

The mechanisms by which nitric oxide (NO) relaxes smooth muscles are unclear. The NO donor sodium nitroprusside (SNP) has been reported to increase the Ca2+ release frequency (Ca2+ sparks) through ryanodine receptors (RyRs) and activate spontaneous transient outward currents (STOCs), resulting in smooth muscle relaxation. Our findings that caffeine relaxes and hyperpolarizes murine gastric fundus smooth muscles and increases phospholamban (PLB) phosphorylation by Ca2+/calmodulin (CaM)-dependent protein kinase II (CaM kinase II) suggest that PLB phosphorylation by CaM kinase II participates in smooth muscle relaxation by increasing sarcoplasmic reticulum (SR) Ca2+ uptake and the frequencies of SR Ca2+ release events and STOCs. Thus, in the present study, we investigated the roles of CaM kinase II and PLB in SNP-induced relaxation of murine gastric fundus smooth muscles. SNP hyperpolarized and relaxed gastric fundus circular smooth muscles and activated CaM kinase II. SNP-induced CaM kinase II activation was prevented by KN-93. Ryanodine, tetracaine, 2-aminoethoxydiphenylborate, and cyclopiazonic acid inhibited SNP-induced fundus smooth muscle relaxation and CaM kinase II activation. The Ca2+-activated K+ channel blockers iberiotoxin and apamin inhibited SNP-induced hyperpolarization and relaxation. The soluble guanylate cyclase inhibitor 1 H-[1,2,4]oxadiazolo-[4,3-α]quinoxalin-1-one inhibited SNP-induced relaxation and CaM kinase II activation. The membrane-permeable cGMP analog 8-bromo-cGMP relaxed gastric fundus smooth muscles and activated CaM kinase II. SNP increased phosphorylation of PLB at Ser16 and Thr17. Thr17 phosphorylation of PLB was inhibited by cyclopiazonic acid and KN-93. Ser16 and Thr17 phosphorylation of PLB was sensitive to 1 H-[1,2,4]oxadiazolo-[4,3-α]quinoxalin-1-one. These results demonstrate a novel pathway linking the NO-soluble guanylyl cyclase-cGMP pathway, SR Ca2+ release, PLB, and CaM kinase II to relaxation in gastric fundus smooth muscles.

Regulation of cGMP-induced relaxation and cGMP-dependent protein kinase in rat myometrium during pregnancy

1998 ◽  
Vol 274 (3) ◽  
pp. C748-C756 ◽  
Author(s):  
R. Ann Word ◽  
Trudy L. Cornwell
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Ovariectomized Rats ◽  
Smooth Muscle Relaxation ◽  
Dependent Protein Kinase ◽  
Pregnant Rats ◽  
Aortic Smooth Muscle ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
High Concentrations

Increases in guanosine 3′,5′-cyclic monophosphate (cGMP) induced by nitric oxide (NO), nitrovasodilators, and atrial peptides correlate with relaxation of vascular smooth muscle. Relaxation of myometrial smooth muscle by increases in cGMP, however, has required unusually high concentrations of the cyclic nucleotide. We tested the hypothesis that the sensitivity of myometrium to relaxation by cGMP is increased during pregnancy. Aortic smooth muscle was more sensitive to relaxation by cGMP than myometrial tissues, and, contrary to our hypothesis, myometrium from pregnant rats was least sensitive. Although levels of cGMP were elevated after treatment with the NO donor, S-nitroso- N-acetylpenicillamine, relaxation of myometrial tissues obtained from pregnant rats occurred only at extraordinarily high concentrations. The levels of cGMP-dependent protein kinase (PKG) were significantly decreased in myometrium from pregnant rats compared with myometrium from nonpregnant cycling animals or aortic smooth muscle. Administration of estradiol to ovariectomized rats increased myometrial PKG expression, and progesterone antagonized this response. We conclude that 1) myometrial tissues from pregnant rats are not sensitive to relaxation by cGMP and 2) this insensitivity to cGMP is accompanied by progesterone-mediated decreases in the level of PKG expression.

scholarly journals Involvement of cGMP-dependent protein kinase in the relaxation of ovine pulmonary arteries to cGMP and cAMP

2000 ◽  
Vol 88 (5) ◽  
pp. 1637-1642 ◽  
Author(s):  
Srinivas N. Dhanakoti ◽  
Yuansheng Gao ◽  
Minh Q. Nguyen ◽  
J. Usha Raj
Keyword(s):  
Protein Kinase ◽  
Muscle Relaxation ◽  
Pulmonary Arteries ◽  
Smooth Muscle Relaxation ◽  
Dependent Protein Kinase ◽  
Pulmonary Vasodilation ◽  
Dependent Protein ◽  
Pulmonary Arterial ◽  
Relaxation Responses

Agonist-induced smooth muscle relaxation occurs following an increase in intracellular concentrations of cGMP or cAMP. However, the role of protein kinase G (PKG) and/or protein kinase A (PKA) in cGMP- or cAMP-mediated pulmonary vasodilation is not clearly elucidated. In this study, we examined the relaxation responses of isolated pulmonary arteries of lambs (age = 10 ± 1 days), preconstricted with endothelin-1, to increasing concentrations of 8-bromo-cGMP (8-BrcGMP) or 8-BrcAMP (cell-permeable analogs), in the presence or absence of Rp-8-β-phenyl-1, N 2-etheno-bromoguanosine cyclic monosphordthioate ( Rp-8-PET-BrcGMPS) or KT-5720, selective inhibitors of PKG and PKA, respectively. When examined for specificity, Rp-8-Br-PET-cGMPS abolished PKG, but not PKA, activity in pulmonary arterial extracts, whereas KT-5720 inhibited PKA activity only. 8-BrcGMP-induced relaxation was inhibited by the PKG inhibitor only, whereas 8-BrcAMP-induced relaxation was inhibited by both inhibitors. A nearly fourfold higher concentration of cAMP than cGMP was required to relax arteries by 50% and to activate PKG by 50%. Our results demonstrate that relaxation of pulmonary arteries is more sensitive to cGMP than cAMP and that PKG plays an important role in both cGMP- and cAMP-mediated relaxation.

Activation of phosphodiesterase 5 and inhibition of guanylate cyclase by cGMP-dependent protein kinase in smooth muscle

2001 ◽  
Vol 360 (1) ◽  
pp. 199-208 ◽  
Author(s):  
Karnam S. MURTHY
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Guanylate Cyclase ◽  
Kinase Inhibitor ◽  
Soluble Guanylate Cyclase ◽  
Feedback Inhibition ◽  
No Donor ◽  
Allosteric Sites ◽  
Dependent Protein

The regulation of cGMP-specific phosphodiesterase (PDE) 5 and soluble guanylate cyclase (GC) by cGMP- and cAMP-dependent protein kinases (PKG and PKA respectively) was examined in gastric smooth muscle. The NO donor, sodium nitroprusside (SNP), stimulated PDE5 phosphorylation and activity, which was blocked by the selective PKG inhibitor, KT5823, resulting in an elevation of cGMP levels. Activation of PKA either directly by Sp-5,6-dichloro-1-β-d-ribofuranosyl benzimidazole 3′,5′-cyclic monophosphothioate, or via isoproterenol- and forskolin-dependent increase in cAMP, also caused an increase in PDE5 phosphorylation and activity, but only in the presence of cGMP; consistent with the dependence of PDE5 phosphorylation and activity on cGMP binding to allosteric sites in the regulatory domain of PDE5. The selective PKA inhibitors, myristoylated protein kinase inhibitor and H-89, blocked the increase in PDE5 phosphorylation and activity induced by PKA. SNP also stimulated soluble GC phosphorylation and activity. KT5823 abolished phosphorylation and augmented soluble GC activity, implying feedback inhibition of soluble GC by PKG-dependent phosphorylation. Phosphorylation by PKG was direct and could be induced in vitro. Activation of PKA had no effect on soluble GC. Thus cGMP levels are regulated by PKG- and PKA-dependent activation of PDE5 and PKG-specific inhibition of soluble GC.

A primary role for protein kinase A in smooth muscle relaxation induced by adrenergic agonists and neuropeptides

1992 ◽  
Vol 263 (3) ◽  
pp. G360-G364 ◽  
Author(s):  
Z. F. Gu ◽  
R. T. Jensen ◽  
P. N. Maton
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Primary Role ◽  
Adrenergic Agents ◽  
Competitive Antagonism ◽  
Gastric Smooth Muscle ◽  
Kinase A

Many studies suggest that smooth muscle relaxation caused by beta-adrenergic agents and various neuropeptides occurs as a result of an increase in cellular adenosine 3',5'-cyclic monophosphate (cAMP). However, the evidence is indirect, and furthermore does not demonstrate that an increase in cAMP is essential for mediating relaxation. To define more clearly the role of cAMP in receptor-mediated smooth muscle relaxation, we used a specific competitive antagonist of the action of cAMP on protein kinase A, (R)-p-adenosine 3',5'-cyclic phosphorothioate [(R)-p-cAMPS], and its S isomer, (S)-p-cAMPS, which functions as a cAMP agonist. In gastric smooth muscle cells from guinea pig, (S)-p-cAMPS caused a dose-related relaxation [50% inhibitory concentration (IC50) 86 +/- 59 nM]. Vasoactive intestinal peptide (VIP) produced smooth muscle cell relaxation (IC50 2.3 +/- 0.8 nM) through occupation of specific VIP receptors. (R)-p-cAMPS inhibited VIP-induced relaxation, with a rightward shift in the VIP dose-response curve, suggesting competitive antagonism. Furthermore, (R)-p-cAMPS inhibited relaxation induced by other agents that increase cellular cAMP (isoproterenol, calcitonin gene-related peptide, and glucagon) but not that induced by ATP or sodium nitroprusside. (R)-p-cAMPS had no effect on contraction stimulated by carbachol, cholecystokinin, or substance P. These data demonstrate that activation of protein kinase A is primarily responsible for mediating gastrin smooth muscle relaxation produced by adrenergic agents and various neuropeptides.

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