ATP‐sensitive K<sup>+</sup> channel activation by calcitonin gene‐related peptide and protein kinase A in pig coronary arterial smooth muscle

Wellman, George C.; Quayle, J. M.; Standen, N B

doi:10.1111/j.1469-7793.1998.117bu.x

Cited by 157 publications

(159 citation statements)

References 35 publications

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“…In rat aorta [44] and pulmonary artery [45], CGRP interacts with endothelial receptors, stimulating the release of endothelium-derived relaxing factors. By contrast, in cat cerebral [46], pig coronary [47] and rat mesenteric vessels [48], CGRP acts directly on VSMCs. Recently, Zhou et al reported that CGRP inhibits angiotensin II-induced endothelial progenitor cell senescence by upregulating klotho expression [49].…”

Section: Discussionmentioning

confidence: 99%

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

Yang

Sakurai

Kamiyoshi

et al. 2013

Journal of Molecular and Cellular Cardiology

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Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after percutaneous coronary intervention. Calcitonin gene-related peptide (CGRP) is produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene.Originally identified as a strongly vasodilatory neuropeptide, CGRP is now known to be a pleiotropic peptide widely distributed in various organs and tissues. Our aim was to investigate the possibility that CGRP acts as an endogenous vasoprotective molecule.We compared the effect of CGRP deficiency on neointima formation after wire-induced vascular injury in wild-type and CGRP knockout (CGRP-/-) mice. We found that neointima formation after vascular injury was markedly enhanced in CGRP-/-mice, which also showed a higher degree of oxidative stress, as indicated by reduced expression of nitric oxide synthase, increased expression of p47phox, and elevated levels of 4HNE, as well as greater infiltration of macrophages. In addition, CGRP-deficiency led to increased vascular smooth muscle cell (VSMC) proliferation within the neointima. By contrast, bone marrow-derived cells had little or no effect on neointima formation in CGRP-/-mice. In vitro analysis showed CGRP-treatment suppressed VSMC proliferation, migration, and ERK1/2 activity. These results clearly demonstrate that endogenous CGRP suppresses the oxidative stress and VSMC proliferation induced by vascular injury. As a vasoprotective molecule, CGRP could be an important therapeutic target in cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

Yang

Sakurai

Kamiyoshi

et al. 2013

Journal of Molecular and Cellular Cardiology

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“…Several groups of channel openers activate the channel, including pharmacological K ATP channel openers (KCOs, e.g. pinacidil and nicorandil) (12), metabolites (MgADP, acidosis) (13,14), and hormonal vasodilators and neurotransmitters (calcitonin gene-related peptide, epoxyeicosatrienoic acids, ␤-adrenergic receptor agonists, and vasoactive intestinal polypeptide) (5,(15)(16)(17). KCOs and Mg 2ϩ nucleotides activate the K ATP channels via binding to the SUR subunits (12,18).…”

mentioning

confidence: 99%

cAMP-dependent Protein Kinase Phosphorylation Produces Interdomain Movement in SUR2B Leading to Activation of the Vascular KATP Channel

Shi

Chen

et al. 2008

Journal of Biological Chemistry

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Vascular ATP-sensitive K ؉ channels are activated by multiple vasodilating hormones and neurotransmitters via PKA. A critical PKA phosphorylation site (Ser-1387) is found in the second nucleotide-binding domain (NBD 2 ) of the SUR2B subunit. To understand how phosphorylation at Ser-1387 leads to changes in channel activity, we modeled the SUR2B using a newly crystallized ABC protein SAV1866. The model showed that Ser-1387 was located on the interface of NBD2 with TMD1 and physically interacted with Tyr-506 in TMD1. A positively charged residue (Arg-1462) in NBD2 was revealed in the close vicinity of Ser-1387. Mutation of either of these three residues abolished PKA-dependent channel activation. Molecular dynamics simulations suggested that Ser-1387, Tyr-506, and Arg-1462 formed a compact triad upon Ser-1387 phosphorylation, leading to reshaping of the NBD2 interface and movements of NBD2 and TMD1. Restriction of the interdomain movements by engineering a disulfide bond between TMD1 and NBD2 prevented the channel activation in a redox-dependent manner. Thus, a channel-gating mechanism is suggested through enhancing the NBD-TMD coupling efficiency following Ser-1387 phosphorylation, which is shared by multiple vasodilators.

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“…thus, we focused on the involvement of K atp channels in the prostatic relaxation induced by loperamide. We then applied forskolin as a positive reference since forskolin was introduced as a direct activator of adenylate cyclase which can increase the intracellular cyclic amp (camp) to activate camp-dependent protein kinase (pKa) for opening K atp channels (23).…”

Section: Discussionmentioning

confidence: 99%

“…the prostatic relaxation of forskolin was abolished by h-89 at a concentration sufficient to block PKA (23) and was enhanced by IBMX at a concentration sufficient to inhibit cAMPphosphodiesterase (22). Similar results were also observed in prostate strips relaxed by loperamide (table ii).…”

Section: Discussionmentioning

confidence: 99%

“…in prostate strips precontracted with phenylephrine (1 µmol/l) or Kcl (50 mmol/l), forskolin-induced relaxation was also abolished by pretreatment with glibenclamide (1 µmol/l). moreover, prostatic relaxation by forskolin was increased by 3-isobutyl-1-methylxanthine (iBmx) at a concentration (10 µmol/l) sufficient to inhibit cAMP-phosphodiesterase (22), and was decreased by h-89 at a concentration (1 µmol/l) enough to abolish the protein kinase a (pKa) (23 loperamide-induced prostatic relaxation was also modified by these agents in a similar manner. results showed that prostatic relaxation induced by loperamide was increased by iBmx and attenuated by h-89 (table ii).…”

Section: Role Of Atp-sensitive K + (K Atpmentioning

confidence: 99%

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Prostatic relaxation induced by loperamide is mediated through activation of opioid μ-2 receptors in vitro

Lu¹,

Chung²

2011

Experimental and Therapeutic Medicine

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Abstract. the merit of opioid µ-receptor activation in the improvement of benign prostatic hyperplasia (Bph) remains obscure. in the present study, we used loperamide to identify the subtype of opioid µ-receptors involved in prostatic relaxation and investigate the possible mechanism of this relaxation. prostate strips were isolated from 12-week-old male Wistar rats for identification of isometric tension. The prostate strips were precontracted with either 1 µmol/l phenylephrine or 50 mmol/l Kcl. the decrease in muscle tone (relaxation) was then characterized after cumulative administration of loperamide (0.1 to 10 µmol/l) into the organ bath for the concentration-dependent study. Pretreatment with specific blockers or antagonists was carried out to compare the changes in loperamide-induced relaxation. loperamide produced a marked relaxation in the isolated prostates precontracted with phenylephrine or Kcl in a dose-dependent manner. this relaxation was abolished by cyprodime, a selective opioid µ-receptor antagonist, but was not modified by naloxonazine at a dose sufficient to block the opioid µ-1 receptors. treatment with an agonist for opioid µ-1 receptors also failed to modify the muscle tone. moreover, the relaxation by loperamide was attenuated by glibenclamide at a dose sufficient to block ATP-sensitive K + channels. in addition, this action of loperamide was abolished by protein kinase a (pKa) inhibitor and enhanced by the inhibitor of phosphodiesterase for cyclic amp (camp). Our results suggest that loperamide induces prostatic relaxation through activation of opioid µ-2 receptors via the camp-pKa pathway to open atp-sensitive K + channels. IntroductionBenign prostatic hyperplasia (Bph) occurs frequently in older men and is associated with lower urinary tract symptoms causing obstruction of the proximal urethra and urinary flow disturbances (1). In clinics, medical treatments for BPH include widely used α-1 antagonists and 5-α-reductase inhibitors. however, the side effects, such as postural hypotension, erectile dysfunction and ejaculatory difficulty, disturb the quality of life of these patients (2,3). therefore, development of a more effective therapy for the treatment of Bph is urgent and necessary.loperamide is widely used in the clinic for a variety of diarrheal syndromes, including acute and nonspecific (infectious) diarrhea (4,5). Recently, we identified opioid µ-receptor expression in rat prostates, and prostatic relaxation was induced by the activation of opioid µ-receptors using loperamide (6). loperamide was introduced as a peripheral agonist of opioid µ-receptors with poor ability to penetrate the bloodbrain barrier (7,8). Some analgesic agents have also revealed relaxant effects in smooth muscle (9,10). (+)-tramadol was found to activate peripheral opioid µ-receptors to exhibit a concentration-dependent relaxation of aorta (11). Basically, the opioid µ-receptors have been divided into 3 subtypes, including µ-1, µ-2 and µ-3 opioid receptors (12). however, activation of opioid µ-1 receptors ...

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ATP‐sensitive K⁺ channel activation by calcitonin gene‐related peptide and protein kinase A in pig coronary arterial smooth muscle

Cited by 157 publications

References 35 publications

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

cAMP-dependent Protein Kinase Phosphorylation Produces Interdomain Movement in SUR2B Leading to Activation of the Vascular KATP Channel

Prostatic relaxation induced by loperamide is mediated through activation of opioid μ-2 receptors in vitro

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ATP‐sensitive K+ channel activation by calcitonin gene‐related peptide and protein kinase A in pig coronary arterial smooth muscle

Cited by 157 publications

References 35 publications

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

cAMP-dependent Protein Kinase Phosphorylation Produces Interdomain Movement in SUR2B Leading to Activation of the Vascular KATP Channel

Prostatic relaxation induced by loperamide is mediated through activation of opioid μ-2 receptors in vitro

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ATP‐sensitive K⁺ channel activation by calcitonin gene‐related peptide and protein kinase A in pig coronary arterial smooth muscle