β 2 -Adrenergic Stimulation Compartmentalizes β 1 Signaling Into Nanoscale Local Domains by Targeting the C-Terminus of β 1 -Adrenoceptors

βARs (β-adrenergic receptors) are prototypical GPCRs (G protein-coupled receptors) that play a pivotal role in sympathetic regulation. In heart cells, β AR signaling mediates a global response, including both l-type Ca channels in the sarcolemma/T tubules and RyRs (ryanodine receptors) in the SR (sa...

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Published inCirculation research Vol. 124; no. 9; pp. 1350 - 1359
Main Authors 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
Format Journal Article
LanguageEnglish
Published United States 26.04.2019
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Abstract βARs (β-adrenergic receptors) are prototypical GPCRs (G protein-coupled receptors) that play a pivotal role in sympathetic regulation. In heart cells, β AR signaling mediates a global response, including both l-type Ca channels in the sarcolemma/T tubules and RyRs (ryanodine receptors) in the SR (sarcoplasmic reticulum). In contrast, β AR mediates local signaling with little effect on the function of SR proteins. To investigate the signaling relationship between β ARs and β ARs. Using whole-cell patch-clamp analyses combined with confocal Ca imaging, we found that the activation of compartmentalized β AR signaling was able to convert the β AR signaling from global to local mode, preventing β ARs from phosphorylating RyRs that were only nanometers away from sarcolemma/T tubules. This offside compartmentalization was eliminated by selective inhibition of β AR, GRK2 (GPCR kinase-2), βarr1 (β-arrestin-1), and phosphodiesterase-4. A knockin rat model harboring mutations of the last 3 serine residues of the β AR C terminus, a component of the putative βarr1 binding site and GRK2 phosphorylation site, eliminated the offside compartmentalization conferred by β AR activation. β AR stimulation compartmentalizes β AR signaling into nanoscale local domains in a phosphodiesterase-4-dependent manner by targeting the C terminus of β ARs. This finding reveals a fundamental negative feed-forward mechanism that serves to avoid the cytotoxicity of circulating catecholamine and to sharpen the transient β AR response of sympathetic excitation.
AbstractList βARs (β-adrenergic receptors) are prototypical GPCRs (G protein-coupled receptors) that play a pivotal role in sympathetic regulation. In heart cells, β AR signaling mediates a global response, including both l-type Ca channels in the sarcolemma/T tubules and RyRs (ryanodine receptors) in the SR (sarcoplasmic reticulum). In contrast, β AR mediates local signaling with little effect on the function of SR proteins. To investigate the signaling relationship between β ARs and β ARs. Using whole-cell patch-clamp analyses combined with confocal Ca imaging, we found that the activation of compartmentalized β AR signaling was able to convert the β AR signaling from global to local mode, preventing β ARs from phosphorylating RyRs that were only nanometers away from sarcolemma/T tubules. This offside compartmentalization was eliminated by selective inhibition of β AR, GRK2 (GPCR kinase-2), βarr1 (β-arrestin-1), and phosphodiesterase-4. A knockin rat model harboring mutations of the last 3 serine residues of the β AR C terminus, a component of the putative βarr1 binding site and GRK2 phosphorylation site, eliminated the offside compartmentalization conferred by β AR activation. β AR stimulation compartmentalizes β AR signaling into nanoscale local domains in a phosphodiesterase-4-dependent manner by targeting the C terminus of β ARs. This finding reveals a fundamental negative feed-forward mechanism that serves to avoid the cytotoxicity of circulating catecholamine and to sharpen the transient β AR response of sympathetic excitation.
Author Wang, Xiao-Ting
Yang, Hua-Qian
Wang, Yu-Pu
Xiao, Rui-Ping
Gong, Yun-Yun
Zhu, Si-Yu
Liu, Xiao-Xiao
Wang, Li-Peng
Xing, Xin
Hou, TingTing
Fan, Xue-Xin
Li, Lin-Lin
Ji, Guang-Shen
Wang, Shi-Qiang
Zhang, Yan
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sarcolemma
sarcoplasmic reticulum
calcium signaling
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Snippet βARs (β-adrenergic receptors) are prototypical GPCRs (G protein-coupled receptors) that play a pivotal role in sympathetic regulation. In heart cells, β AR...
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pubmed
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StartPage 1350
SubjectTerms Adrenergic Agents - pharmacology
Animals
Cells, Cultured
Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism
Male
Mutation
Myocytes, Cardiac - cytology
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Phosphorylation - drug effects
Rats
Rats, Transgenic
Receptors, Adrenergic, beta-1 - chemistry
Receptors, Adrenergic, beta-1 - genetics
Receptors, Adrenergic, beta-1 - metabolism
Receptors, Adrenergic, beta-2 - genetics
Receptors, Adrenergic, beta-2 - metabolism
Ryanodine Receptor Calcium Release Channel - metabolism
Sarcolemma - drug effects
Sarcolemma - metabolism
Sarcoplasmic Reticulum - drug effects
Sarcoplasmic Reticulum - metabolism
Signal Transduction - drug effects
Title β 2 -Adrenergic Stimulation Compartmentalizes β 1 Signaling Into Nanoscale Local Domains by Targeting the C-Terminus of β 1 -Adrenoceptors
URI https://www.ncbi.nlm.nih.gov/pubmed/30836825
Volume 124
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