KCTD Family: Emerging Regulators of GPCR Biased Signaling

G protein-coupled receptors (GPCRs) engage multiple transducers to regulate distinct physiological processes. These transducers include various G proteins subtypes, GPCR kinases (GRKs), and β-arrestins. In addition to promoting receptor desensitization, β-arrestins serve as scaffolds for signaling via non-G protein pathways. Biased signaling enables GPCRs to selectively engage specific transducers, typically through different conformational states of GPCRs. While significant focus has been placed on developing biased ligands that preferentially activate specific G proteins or β-arrestins, the strategy focused on modulating particular G protein subunits (Gα versus βγ) remains underexplored. Recently, members of the KCTD (potassium channel tetramerization domain-containing) family have emerged as critical regulators of GPCR signaling, particularly through their roles in mediating Gβγ degradation or uncoupling Gβγ from downstream effectors. This ability positions the KCTD family as potential targets for selectively modulating Gβγ signaling with minimal impact on Gα-mediated pathways. In this chapter, we introduce the KCTD family, summarize current knowledge of their role in GPCR signaling regulation, and highlight unsolved questions in existing models, along with directions for future research.