PKA-dependent activation of the vascular smooth muscle isoform of KATP channels by vasoactive intestinal polypeptide and its effect on relaxation of the mesenteric resistance artery

Yang, Yang; Shi, Yun; Guo, Shouli; Zhang, Shuang; Cui, Ningren; Shi, Weiwei; Zhu, Daling; Jiang, Chun

doi:10.1016/j.bbamem.2007.08.030

Cited by 33 publications

(44 citation statements)

References 56 publications

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“…In rat aortic smooth muscle, however, all potassium channels were reported to be responsible for about 80% relaxation induced by the ER␤ activator diarylpropionitrile (ER␤ selective ligand) and mediated by PKA (68). In rat mesenteric artery, vasoactive intestinal polypeptide caused relaxation through PKA-stimulated K ATP channels (73). Storeoperated Ca 2ϩ entry was also demonstrated to be involved in coronary artery relaxation mediated by a PKA-dependent mechanism under urocortin treatment (62).…”

Section: Discussionmentioning

confidence: 99%

G protein-coupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP

Klussmann

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Yu X, Li F, Klussmann E, Stallone JN, Han G. G proteincoupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP. Am J Physiol Endocrinol Metab 307: E398 -E407, 2014. First published July 8, 2014 doi:10.1152/ajpendo.00534.2013.-Activation of GPER exerts a protective effect in hypertension and ischemia-reperfusion models and relaxes arteries in vitro. However, our understanding of the mechanisms of GPER-mediated vascular regulation is far from complete. In the current study, we tested the hypothesis that GPER-induced relaxation of porcine coronary arteries is mediated via cAMP/PKA signaling. Our findings revealed that vascular relaxation to the selective GPER agonist G-1 (0.3-3 M) was associated with increased cAMP production in a concentration-dependent manner. Furthermore, inhibition of adenylyl cyclase (AC) with SQ-22536 (100 M) or of PKA activity with either Rp-8-CPT-cAMPS (5 M) or PKI (5 M) attenuated G-1-induced relaxation of coronary arteries preconstricted with PGF2␣ (1 M). G-1 also increased PKA activity in cultured coronary artery smooth muscle cells (SMCs). To determine downstream signals of the cAMP/PKA cascade, we measured RhoA activity in cultured human and porcine coronary SMCs and myosin-light chain phosphatase (MLCP) activity in these artery rings by immunoblot analysis of phosphorylation of myosin-targeting subunit protein-1 (p-MYPT-1; the MLCP regulatory subunit). G-1 decreased PGF2␣-induced p-MYPT-1, whereas Rp-8-CPT-cAMPS prevented this inhibitory effect of G-1. Similarly, G-1 inhibited PGF2␣-induced phosphorylation of MLC in coronary SMCs, and this inhibitory effect was also reversed by Rp-8-CPT-cAMPS. RhoA activity was downregulated by G-1, whereas G36 (GPER antagonist) restored RhoA activity. Finally, FMP-API-1 (100 M), an inhibitor of the interaction between PKA and A-kinase anchoring proteins (AKAPs), attenuated the effect of G-1 on coronary artery relaxation and p-MYPT-1. These findings demonstrate that localized cAMP/PKA signaling is involved in GPER-mediated coronary vasodilation by activating MLCP via inhibition of RhoA pathway.

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Section: Discussionmentioning

confidence: 99%

G protein-coupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP

Klussmann

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…The K ATP channels are expressed in almost all tissues. In vascular smooth muscle cells (SMCs), activation of K ATP channels by several vasodilators reduces SMC membrane excitability, leading to vasorelaxation (3,4). Activity of the channels is inhibited by vasoconstrictors (5), resulting in depolarization of the SMCs and vasoconstriction.…”

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confidence: 99%

Oxidative Stress Inhibits Vascular KATP Channels by S-Glutathionylation

Yang¹,

Shi

Cui

et al. 2010

Journal of Biological Chemistry

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The K ATP channel is an important player in vascular tone regulation. Its opening and closure lead to vasodilation and vasoconstriction, respectively. Such functions may be disrupted in oxidative stress seen in a variety of cardiovascular diseases, while the underlying mechanism remains unclear. Here, we demonstrated that S-glutathionylation was a modulation mechanism underlying oxidant-mediated vascular K ATP channel regulation. An exposure of isolated mesenteric rings to hydrogen peroxide (H 2 O 2 ) impaired the K ATP channel-mediated vascular dilation. In whole-cell recordings and inside-out patches, H 2 O 2 or diamide caused a strong inhibition of the vascular K ATP channel (Kir6.1/SUR2B) in the presence, but not in the absence, of glutathione (GSH). Similar channel inhibition was seen with oxidized glutathione (GSSG) and thiol-modulating reagents. The oxidant-mediated channel inhibition was reversed by the reducing agent dithiothreitol (DTT) and the specific deglutathionylation reagent glutaredoxin-1 (Grx1). Consistent with S-glutathionylation, streptavidin pull-down assays with biotinylated glutathione ethyl ester (BioGEE) showed incorporation of GSH to the Kir6.1 subunit in the presence of H 2 O 2 . These results suggest that S-glutathionylation is an important mechanism for the vascular K ATP channel modulation in oxidative stress.

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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).…”

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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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PKA-dependent activation of the vascular smooth muscle isoform of KATP channels by vasoactive intestinal polypeptide and its effect on relaxation of the mesenteric resistance artery

Cited by 33 publications

References 56 publications

G protein-coupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP

G protein-coupled estrogen receptor 1 mediates relaxation of coronary arteries via cAMP/PKA-dependent activation of MLCP

Oxidative Stress Inhibits Vascular KATP Channels by S-Glutathionylation

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

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