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

• Published in: Circulation 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
• Language: English
• Published: United States 26.04.2019
• Subjects: 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; serine; phosphorylation; sarcolemma; sarcoplasmic reticulum; calcium signaling
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.118.314322

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.