[PMID]: | 28696251 |
[Au] Autor: | Zhai X; Leo MD; Jaggar JH |
[Ad] Endereço: | From the Department of Physiology, University of Tennessee Health Science Center, Memphis. |
[Ti] Título: | Endothelin-1 Stimulates Vasoconstriction Through Rab11A Serine 177 Phosphorylation. |
[So] Source: | Circ Res;121(6):650-661, 2017 Sep 01. |
[Is] ISSN: | 1524-4571 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | RATIONALE: Large-conductance calcium-activated potassium channels (BK) are composed of pore-forming BKα and auxiliary ß1 subunits in arterial smooth muscle cells (myocytes). Vasoconstrictors, including endothelin-1 (ET-1), inhibit myocyte BK channels, leading to contraction, but mechanisms involved are unclear. Recent evidence indicates that BKα is primarily plasma membrane localized, whereas the cellular location of ß1 can be rapidly altered by Rab11A-positive recycling endosomes. Whether vasoconstrictors regulate the multisubunit composition of surface BK channels to stimulate contraction is unclear. OBJECTIVE: Test the hypothesis that ET-1 inhibits BK channels by altering BKα and ß1 surface trafficking in myocytes, identify mechanisms involved, and determine functional significance in myocytes of small cerebral arteries. METHODS AND RESULTS: ET-1, through activation of PKC (protein kinase C), reduced surface ß1 abundance and the proximity of ß1 to surface BKα in myocytes. In contrast, ET-1 did not alter surface BKα, total ß1, or total BKα proteins. ET-1 stimulated Rab11A phosphorylation, which reduced Rab11A activity. Rab11A serine 177 was identified as a high-probability PKC phosphorylation site. Expression of a phosphorylation-incapable Rab11A construct (Rab11A S177A) blocked the ET-1-induced Rab11A phosphorylation, reduction in Rab11A activity, and decrease in surface ß1 protein. ET-1 inhibited single BK channels and transient BK currents in myocytes and stimulated vasoconstriction via a PKC-dependent mechanism that required Rab11A S177. In contrast, NO-induced Rab11A activation, surface trafficking of ß1 subunits, BK channel and transient BK current activation, and vasodilation did not involve Rab11A S177. CONCLUSIONS: ET-1 stimulates PKC-mediated phosphorylation of Rab11A at serine 177, which inhibits Rab11A and Rab11A-dependent surface trafficking of ß1 subunits. The decrease in surface ß1 subunits leads to a reduction in BK channel calcium-sensitivity, inhibition of transient BK currents, and vasoconstriction. We describe a unique mechanism by which a vasoconstrictor inhibits BK channels and identify Rab11A serine 177 as a modulator of arterial contractility. |
[Mh] Termos MeSH primário: |
Endotelina-1/farmacologia Vasoconstrição Proteínas rab de Ligação ao GTP/metabolismo
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[Mh] Termos MeSH secundário: |
Animais Células Cultivadas Endotelina-1/metabolismo Células HEK293 Seres Humanos Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo Masculino Células Musculares/efeitos dos fármacos Células Musculares/metabolismo Células Musculares/fisiologia Músculo Liso Vascular/metabolismo Músculo Liso Vascular/fisiologia Fosforilação Proteína Quinase C/metabolismo Processamento de Proteína Pós-Traducional Transporte Proteico Ratos Ratos Sprague-Dawley
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Endothelin-1); 0 (Large-Conductance Calcium-Activated Potassium Channels); EC 2.7.11.13 (Protein Kinase C); EC 3.6.1.- (rab11 protein); EC 3.6.5.2 (rab GTP-Binding Proteins) |
[Em] Mês de entrada: | 1709 |
[Cu] Atualização por classe: | 170906 |
[Lr] Data última revisão:
| 170906 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170712 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1161/CIRCRESAHA.117.311102 |
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