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Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gβγ complex

Vanessa L Wehbi1, Hilary P Stevenson, Timothy N Feinstein

  • 1Laboratory for G Protein-Coupled Receptor Biology, Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 9, 2013
PubMed

Insights

Parathyroid hormone receptor type 1 (PTHR) signaling challenges the standard model. Arrestins unexpectedly sustain, rather than block, PTHR-mediated cAMP generation, revealing a new role for arrestins in G protein-coupled receptor signaling.

Area of Science:

  • Cellular signaling
  • Molecular pharmacology
  • Endocrinology

Background:

  • G protein-coupled receptors (GPCRs) mediate transmembrane signaling via G proteins.
  • Arrestins typically terminate GPCR signaling by uncoupling receptors from G proteins.
  • Parathyroid hormone receptor type 1 (PTHR) signaling deviates from this canonical desensitization pathway.

Purpose of the Study:

  • To investigate the unconventional role of β-arrestins in parathyroid hormone receptor type 1 (PTHR) signaling.
  • To resolve the paradox of prolonged cAMP generation despite arrestin binding to PTHR.
  • To elucidate the molecular mechanism underlying sustained PTHR-mediated signaling.

Main Methods:

  • Investigated the formation of ternary complexes involving PTHR, β-arrestin, and Gβγ dimers.
  • Analyzed the kinetics of G protein (G(S)) activation and cAMP generation in response to PTH stimulation.
  • Examined the localization and persistence of arrestin-PTHR complexes on endosomes.

Main Results:

  • PTHR forms a ternary complex with arrestin and Gβγ dimers upon PTH stimulation.
  • This complex accelerates G(S) activation, increasing steady-state levels of activated G(S).
  • Prolonged cAMP generation is observed, correlating with sustained receptor-arrestin-G protein interactions.

Conclusions:

  • Arrestins can sustain GPCR signaling, contradicting the canonical decoupling model.
  • The ternary complex mechanism provides a basis for understanding prolonged PTHR-mediated effects.
  • This discovery redefines the role of arrestins in G protein-coupled receptor signal transduction.

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