scholarly journals Roles of Endothelial Motilin Receptor and Its Signal Transduction Pathway in Motilin-Induced Left Gastric Artery Relaxation in Dogs

2021 ◽  
Vol 12 ◽  
Author(s):  
HongYu Li ◽  
LanLan Yang ◽  
Ying Jin ◽  
ChunXiang Jin
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
G Protein ◽  
Channel Blocker ◽  
Signal Transduction Pathway ◽  
Left Gastric Artery ◽  
Guanosine Monophosphate ◽  
Gastric Artery ◽  
Channel Inhibition ◽  
Motilin Receptor

Background: Motilin increases left gastric artery (LGA) blood flow in dogs via the endothelial motilin receptor (MLNR). This article investigates the signaling pathways of endothelial MLNR.Methods: Motilin-induced relaxation of LGA rings was assessed using wire myography. Nitric oxide (NO), and cyclic guanosine monophosphate (cGMP) levels were measured using an NO assay kit and cGMP ELISA kit, respectively.Results: Motilin concentration-dependently (EC50=9.1±1.2×10−8M) relaxed LGA rings precontracted with U46619 (thromboxane A2 receptor agonist). GM-109 (MLNR antagonist) significantly inhibited motilin-induced LGA relaxation and the production of NO and cGMP. N-ethylmaleimide (NEM; G-protein antagonist), U73122 [phospholipase C (PLC) inhibitor], and 2-aminoethyl diphenylborinate [2-APB; inositol trisphosphate (IP3) blocker] partially or completely blocked vasorelaxation. In contrast, chelerythrine [protein kinase C (PKC) inhibitor] and H89 [protein kinase A (PKA) inhibitor] had no such effect. Low-calcium or calcium-free Krebs solutions also reduced vasorelaxation. N-nitro-L-arginine methyl ester [L-NAME; nitric oxide synthase (NOS) inhibitor] and ODQ [soluble guanylyl cyclase (sGC) inhibitor] completely abolished vasodilation and synthesis of NO and cGMP. Indomethacin (cyclooxygenase inhibitor), 18α-glycyrrhetinic acid [18α-GA; myoendothelial gap junction (MEGJ) inhibitor], and K+ channel inhibition through high K+ concentrations or tetraethylammonium (TEA-Cl; KCa channel blocker) partially decreased vasorelaxation, whereas glibenclamide (KATP channel blocker) had no such effect.Conclusion: The current study suggests that motilin-induced LGA relaxation is dependent on endothelial MLNR through the G protein-PLC-IP3 pathway and Ca2+ influx. The NOS-NO-sGC-cGMP pathway, prostacyclin, MEGJ, and K+ channels (especially KCa) are involved in endothelial-dependent relaxation of vascular smooth muscle (VSM) cells.

scholarly journals The overlooked background of gastric MMC III: the signalling pathways of motilin receptors inducing canine left gastric artery relaxation

2020 ◽  
Author(s):  
Hongyu Li ◽  
Lanlan Yang ◽  
Ying Jin ◽  
Chunxiang Jin
Keyword(s):  
Nitric Oxide ◽  
Signal Transduction ◽  
Endothelial Cells ◽  
Protein Kinase ◽  
Signal Transduction Pathway ◽  
Left Gastric Artery ◽  
Phase Iii ◽  
Dependent Manner ◽  
Transduction Pathway ◽  
Gastric Artery

Abstract Background: In diabetic patients with gastroparesis, the gastric blood supply is often decreased and delayed gastric emptying associating MMCIII absence is the main symptom. Under physiological conditions, motilin has been shown to induce a sustained increase in left gastric artery (LGA) blood flow and initiate MMC phase III simultaneously. The study aimed to elucidating the signal transduction pathways of motilin receptors (MLNRs) in the relaxation of LGA.Methods: MLNR expression in the LGA was analysed by immunohistochemistry. Motilin-induced relaxation of the LGA was tested in a multi-wire myograph system. Effects of inhibitors or blockers in the signal transduction pathway were observed.Results: Immunohistochemical and immunofluorescence staining showed that the MLNRs were on the membranes of endothelial cells. Motilin relaxed U46619 pre-contracted canine LGA rings in a concentration-dependent manner, with an EC50 value of 9.010 ± 0.789 × 10−8 M. Motilin’s effect was inhibited by denuded endothelium but not by muscarinic receptor inhibitors. The effect was selectively and competitively inhibited by Phe-cyclo[Lys-Tyr(3-tBu)-Ala-]•trifluoroacetate (GM-109; MLNR antagonist) and completely or partially inhibited by inhibitors of the G protein–phospholipase C–inositol trisphosphate (G pr–PLC–IP3) and nitric oxide synthase–nitric oxide–soluble guanylyl cyclase (NOS–NO–sGC) signal transduction pathway, inhibitors of cyclooxygenase and myoendothelial gap junction, blockers of the potassium channel and low/free Ca2+ Krebs solutions, but not by inhibitors of protein kinase C, protein kinase A or L-type voltage-operated Ca2+ channel.Conclusions: MLNRs were on the membranes of endothelial cells of canine LGA. The main intracellular signal transduction pathway was motilin–MLNR–G pr–PLC–IP3–NOS–NO–sGC–cGMP. These results may provide a new theoretical basis for research on diabetic gastroparesis.

scholarly journals Cyclic Guanosine Monophosphate Modulates Locomotor Acceleration Induced by Nitric Oxide but not Serotonin in Clione limacina Central Pattern Generator Swim Interneurons

2020 ◽  
Author(s):  
Thomas J Pirtle ◽  
Richard A Satterlie
Keyword(s):  
Nitric Oxide ◽  
Central Pattern Generator ◽  
Guanylyl Cyclase ◽  
Signal Transduction Pathway ◽  
Soluble Guanylyl Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Pattern Generator ◽  
Guanosine Monophosphate ◽  
Cellular Changes ◽  
Clione Limacina

Abstract Typically, the marine mollusk, Clione limacina, exhibits a slow, hovering locomotor gait to maintain its position in the water column. However, the animal exhibits behaviorally relevant locomotor swim acceleration during escape response and feeding behavior. Both nitric oxide and serotonin mediate this behavioral swim acceleration. In this study, we examine the role that the second messenger, cGMP, plays in mediating nitric oxide and serotonin-induced swim acceleration. We observed that the application of an analog of cGMP or an activator of soluble guanylyl cyclase increased fictive locomotor speed recorded from Pd-7 interneurons of the animal’s locomotor central pattern generator. Moreover, inhibition of soluble guanylyl cyclase decreased fictive locomotor speed. These results suggest that basal levels of cGMP are important for slow swimming and that increased production of cGMP mediates swim acceleration in Clione. Because nitric oxide has its effect through cGMP signaling and because we show herein that cGMP produces cellular changes in Clione swim interneurons that are consistent with cellular changes produced by serotonin application, we hypothesize that both nitric oxide and serotonin function via a common signal transduction pathway that involves cGMP. Our results show that cGMP mediates nitric oxide-induced but not serotonin-induced swim acceleration in Clione.

Modulation of Ca(2+)-channel currents by protein kinase C in adult rat sympathetic neurons

1994 ◽  
Vol 72 (4) ◽  
pp. 1549-1560 ◽  
Author(s):  
Y. Zhu ◽  
S. R. Ikeda
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
G Protein ◽  
G Proteins ◽  
Sympathetic Neurons ◽  
Adult Rat ◽  
Kinase C ◽  
Channel Inhibition ◽  
Channel Currents ◽  
Ca2 Channels

1. Modulation of Ca(2+)-channel currents by phorbol-12-myristate-13-acetate (PMA) was investigated in acutely dissociated adult rat superior cervical ganglion neurons using the whole cell variant of the patch-clamp technique. 2. PMA (500 nM) increased the current amplitudes, accelerated the inactivation of step currents, retarded the deactivation of tail currents, and shifted the tail current activation to more negative potentials. 3. The effects of PMA were concentration and voltage dependent and mediated through activation of protein kinase C (PKC). PMA also increased Ca2+ currents recorded with the perforated patch technique. 4. PMA affected the N-type Ca2+ channels and an omega-conotoxin GVIA-resistant current component. Ca2+ currents affected by PMA were not sensitive to omega-agatoxin IVA or nimodipine. 5. PMA not only attenuated Ca(2+)-channel inhibition induced by alpha 2-adrenoceptor agonist, which modulates Ca2+ channels via a pertussis toxin (PTX)-sensitive pathway, but also attenuated current inhibition by vasoactive intestinal polypeptide, which modulates Ca2+ channels via a PTX-insensitive but cholera toxin-sensitive pathway. 6. PMA reversed Ca(2+)-channel inhibition induced by tonic activation of G-protein in the absence of neurotransmitter (even in neurons pretreated with PTX) or induced by activation of G-proteins with guanosine 5'-O-(3-thiotriphosphate) (GTP)-gamma-S. 7. Inhibition of phosphatase by okadaic acid or substitution of Ba2+ for Ca2+ in the external solutions accelerated the PMA effect. 8. Our results suggest that activation of PKC antagonizes G-protein mediated inhibition of Ca2+ channels by shifting Ca2+ channels from the “reluctant” state to the “willing” state. The G-proteins and, more likely, the N-type Ca2+ channels may be the target of PKC phosphorylation. Protein phosphatases may be involved in counteracting the PKC phosphorylation in rat sympathetic neurons.

scholarly journals Possible Participation of Nitric Oxide/Cyclic Guanosine Monophosphate/Protein Kinase C/ATP-Sensitive K+ Channels Pathway in the Systemic Antinociception of Flavokawin B

2011 ◽  
Vol 108 (6) ◽  
pp. 400-405 ◽  
Author(s):  
Azam Shah Mohamad ◽  
Muhammad Nadeem Akhtar ◽  
Shaik Ibrahim Khalivulla ◽  
Enoch Kumar Perimal ◽  
Mohamed Hanief Khalid ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
K Channels ◽  
Kinase C

Second messenger systems as sites of drug action

1992 ◽  
Vol 99 (1-2) ◽  
pp. 1-17
Author(s):  
W. C. Bowman
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Ion Channel ◽  
G Protein ◽  
Inositol Trisphosphate ◽  
Second Messenger ◽  
Drug Action ◽  
Surface Receptors ◽  
Second Messenger Systems ◽  
Near Future

Synopsis:Transmembrane signalling from cell surface receptors occurs by two broad mechanisms: (i) the rapid (ms) direct opening of an ion channel, where the ion channel is a component of the receptor complex (e.g. the nicotinic acetylcholine receptor); and (ii) the more slow (s) modulation of a membrane enzyme or more distant ion channel. Most of the examples of this second mechanism involve a GTP-binding protein or so–called G-protein, and the production of a second messenger. The production of nitric oxide is a special case in that it is eventually produced as a result of the activity of the second messenger ïnositol trisphosphate. The nitric oxide then diffuses into a second cell to give rise to the production of an additional ‘second’ messenger, cyclic GMP.All of the surface receptors themselves exist as a number of subtypes. Additionally, most of the components of the second messenger systems – G-proteins, adenylyl cyclase, guanylyl cyclase, phosphoinositidase, C, inositol trisphosphate receptors, protein kinase A, protein kinase G, protein kinase C, cyclic nucleotide phosphodiesterases, and the enzymes involved in phosphatidylinositol resynthesis – occur in a number of isoforms. Furthermore, all the enzymes are controlled in their activity by a number of co-factors and other modulators. This diversity provides the potential for selective drug action, a potential which is already being exploited and which will be increasingly so in the near future.

Role of prostaglandins and nitric oxide in gastrointestinal hyperemia of diabetic rats

1996 ◽  
Vol 270 (4) ◽  
pp. G684-G690 ◽  
Author(s):  
E. Goldin ◽  
M. Casadevall ◽  
M. Mourelle ◽  
I. Cirera ◽  
J. I. Elizalde ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Gastric Mucosa ◽  
Superior Mesenteric Artery ◽  
Mesenteric Artery ◽  
Left Gastric Artery ◽  
Diabetic Rats ◽  
Gastric Artery ◽  
Blood Flows ◽  
And Control

The aim of the study was to characterize the gastric and mesenteric vascular changes induced by diabetes and the implication of endothelial [nitric oxide (NO) and prostaglandins] and humoral (glucagon) factors in such changes. Diabetes was induced in rats by a single streptozotocin injection. Four weeks later, gastric mucosa, left gastric artery, and superior mesenteric artery blood flows were measured using hydrogen gas clearance and perivascular ultrasonic flowmeter techniques, respectively, in anesthetized and fasted diabetic and control rats. Blood pressure, hematocrit, blood volume, and blood viscosity were also measured. Left gastric (41 +/- 6 vs. 25 +/- 4 ml.min-1.100 g-1) and superior mesenteric artery blood flows (83 +/- 8 vs. 65 +/- 4 ml.min-1.100 g-1) were significantly higher in diabetic than in control rats. The increased blood flow in the left gastric artery was distributed to a hypertrophic mucosa in diabetic rats; therefore, the blood flow per 100 g tissue in the gastric mucosa was not significantly different in diabetic compared with control rats. Pretreatment with indomethacin reduced both increase gastric and mesenteric flows of the diabetic rats to the same levels as in control rats. NG-nitro-L-arginine methyl ester decreased gastric blood flow in a dose-dependent manner and to a similar extent in diabetic and control rats. In contrast, an increased sensitivity to the higher doses of the NO inhibitor was observed in the mesenteric vascular bed of diabetic rats. Glucagon reduction achieved by somatostatin infusion did not influence either gastric or mesenteric blood flow in diabetic rats. In summary, the present study revealed an increase in gastric and mesenteric arterial blood flows in streptozotocin-induced diabetic rats. The gastrointestinal hyperemia seems to be due, at least in part, to the increased demand of a hypertrophic mucosa and is mediated primarily by endogenous prostaglandins. Increased vascular sensitivity to NO may also contribute to the mesenteric vasodilation.

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