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<p>G protein-coupled receptors (GPCRs) are targets for almost a third of all FDA-approved drugs. GPCRs are known to signal through both heterotrimeric G proteins and β-arrestins. Traditionally these pathways were viewed as largely separable, with G proteins primarily initiating downstream signaling while β-arrestins modulate receptor trafficking and desensitization in addition to regulating their own signaling events. Recent studies suggest an integrated role of G proteins and β-arrestins in GPCR signaling, however the cellular and biochemical requirements for G protein:β-arrestin interactions remain unclear. Here, we show that G proteins and β-arrestins can directly interact. Through utilization of β-arrestin-biased receptors and artificially enforced β-arrestin relocalization, we demonstrate that recruitment of β-arrestin to the plasma membrane is sufficient to interact with the G protein Gαi. Using purified proteins, we show that Gαi directly interacts with β-arrestin. In addition, we find that Gαi family members differ in their degree of association with β-arrestin, and that a large degree of this selectivity resides within the alpha helical domain of Gαi. These findings delineate the cellular and biochemical conditions that drive direct interactions between G proteins and β-arrestins and illuminate the molecular basis for how they interact.</p>

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β-arrestin recruitment facilitates a direct association with G proteins

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月17日

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  • Claudia Y. Lee,
  • Jeffrey S. Smith,
  • Taylor Kohlmann,
  • Emily M. Meara,
  • Uyen Pham,
  • Frank Kwarcinski,
  • Andrew N. Dates,
  • Jessica K. Orofino,
  • Issac Choi,
  • Ari S. Hilibrand,
  • Chanpreet Jassal,
  • Abigail Gilmer,
  • Stephen C. Blacklow,
  • Gregory G. Tall,
  • Andrew C. Kruse,
  • Sudarshan Rajagopal

摘要

G protein-coupled receptors (GPCRs) are targets for almost a third of all FDA-approved drugs. GPCRs are known to signal through both heterotrimeric G proteins and β-arrestins. Traditionally these pathways were viewed as largely separable, with G proteins primarily initiating downstream signaling while β-arrestins modulate receptor trafficking and desensitization in addition to regulating their own signaling events. Recent studies suggest an integrated role of G proteins and β-arrestins in GPCR signaling, however the cellular and biochemical requirements for G protein:β-arrestin interactions remain unclear. Here, we show that G proteins and β-arrestins can directly interact. Through utilization of β-arrestin-biased receptors and artificially enforced β-arrestin relocalization, we demonstrate that recruitment of β-arrestin to the plasma membrane is sufficient to interact with the G protein Gαi. Using purified proteins, we show that Gαi directly interacts with β-arrestin. In addition, we find that Gαi family members differ in their degree of association with β-arrestin, and that a large degree of this selectivity resides within the alpha helical domain of Gαi. These findings delineate the cellular and biochemical conditions that drive direct interactions between G proteins and β-arrestins and illuminate the molecular basis for how they interact.