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ß2-Adrenergic Stimulation Compartmentalizes ß1 Signaling Into Nanoscale Local Domains by Targeting the C-Terminus of ß1-Adrenoceptors.
Yang, Hua-Qian; Wang, Li-Peng; Gong, Yun-Yun; Fan, Xue-Xin; Zhu, Si-Yu; Wang, Xiao-Ting; Wang, Yu-Pu; Li, Lin-Lin; Xing, Xin; Liu, Xiao-Xiao; Ji, Guang-Shen; Hou, TingTing; Zhang, Yan; Xiao, Rui-Ping; Wang, Shi-Qiang.
Afiliação
  • Yang HQ; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Wang LP; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Gong YY; Beijing Advanced Innovation Center for Biomedical Engineering, and School of Biological Science and Medical Engineering, Beihang University, Beijing, China (Y.-Y.G).
  • Fan XX; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Zhu SY; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Wang XT; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Wang YP; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Li LL; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Xing X; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Liu XX; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Ji GS; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Hou T; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Zhang Y; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Xiao RP; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
  • Wang SQ; From the State Key Lab of Membrane Biology, College of Life Sciences and Institute of Molecular Medicine, Peking University, Beijing, China (H.-Q.Y., L.-P.W., X.-X.F., S.-Y.Z., X.-T.W., Y.-P.W., L.-L.L., X.X., X.-X.L., G.-S.J., T.T.H., Y.Z., R.-P.X., S.-Q.W.).
Circ Res ; 124(9): 1350-1359, 2019 04 26.
Article em En | MEDLINE | ID: mdl-30836825
ABSTRACT
RATIONALE ßARs (ß-adrenergic receptors) are prototypical GPCRs (G protein-coupled receptors) that play a pivotal role in sympathetic regulation. In heart cells, ß1AR signaling mediates a global response, including both l-type Ca2+ channels in the sarcolemma/T tubules and RyRs (ryanodine receptors) in the SR (sarcoplasmic reticulum). In contrast, ß2AR mediates local signaling with little effect on the function of SR proteins.

OBJECTIVE:

To investigate the signaling relationship between ß1ARs and ß2ARs. METHOD AND

RESULTS:

Using whole-cell patch-clamp analyses combined with confocal Ca2+ imaging, we found that the activation of compartmentalized ß2AR signaling was able to convert the ß1AR signaling from global to local mode, preventing ß1ARs from phosphorylating RyRs that were only nanometers away from sarcolemma/T tubules. This offside compartmentalization was eliminated by selective inhibition of ß2AR, GRK2 (GPCR kinase-2), ßarr1 (ß-arrestin-1), and phosphodiesterase-4. A knockin rat model harboring mutations of the last 3 serine residues of the ß1AR C terminus, a component of the putative ßarr1 binding site and GRK2 phosphorylation site, eliminated the offside compartmentalization conferred by ß2AR activation.

CONCLUSIONS:

ß2AR stimulation compartmentalizes ß1AR signaling into nanoscale local domains in a phosphodiesterase-4-dependent manner by targeting the C terminus of ß1ARs. This finding reveals a fundamental negative feed-forward mechanism that serves to avoid the cytotoxicity of circulating catecholamine and to sharpen the transient ß1AR response of sympathetic excitation.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores Adrenérgicos beta 2 / Receptores Adrenérgicos beta 1 / Canal de Liberação de Cálcio do Receptor de Rianodina Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores Adrenérgicos beta 2 / Receptores Adrenérgicos beta 1 / Canal de Liberação de Cálcio do Receptor de Rianodina Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article