A docking site for G protein βγ subunits on the parathyroid hormone 1 receptor supports signaling through multiple pathways

Mol Endocrinol. 2006 Jan;20(1):136-46. doi: 10.1210/me.2005-0169. Epub 2005 Aug 11.


The G protein-coupled receptor for PTH and PTH-related protein (PTH1R) signals via many intracellular pathways. The purpose of this work is to investigate a G protein binding site on an intracellular domain of the PTH1R. The carboxy-terminal, cytoplasmic tail of the PTH1R fused to glutathione-S-transferase interacts with Gi/o proteins in vitro. All three subunits of the heterotrimer interact with the receptor C-tail. Activation of the heterotrimeric complex with GTPgammaS has no effect on Gbetagamma interactions, but markedly disrupts binding of the Galphai/o subunits to the receptor tail, suggesting that direct Gbetagamma binding indirectly links Galpha subunits to this region of the receptor. Gbetagamma subunits alone bind the C-tail with an affinity that is comparable to the heterotrimeric G protein complex. G protein complexes consisting of Galphashis6-beta1gamma2 and Galphaqhis6-beta1gamma2 also interact with the PTH1R tail in vitro. The Gbetagamma interaction domain is located on the juxta-membrane region of the tail between amino acids 468 and 491. Mutations that disrupt Gbetagamma interactions block PTH signaling via phospholipase Cbeta/[Ca2+]i and MAPK and markedly reduce signaling via adenylyl cyclase/cAMP. Herein, we define a domain on the PTH1R that is capable of binding G protein heterotrimeric complexes via direct Gbetagamma interactions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Calcium / metabolism
  • Cell Line
  • Cyclic AMP / metabolism
  • Dimerization
  • GTP-Binding Protein beta Subunits / genetics
  • GTP-Binding Protein beta Subunits / metabolism*
  • GTP-Binding Protein gamma Subunits / genetics
  • GTP-Binding Protein gamma Subunits / metabolism*
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacology
  • Humans
  • Isoenzymes / metabolism
  • MAP Kinase Signaling System / physiology
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Phospholipase C beta
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Receptor, Parathyroid Hormone, Type 1 / genetics
  • Receptor, Parathyroid Hormone, Type 1 / metabolism*
  • Signal Transduction
  • Type C Phospholipases / metabolism


  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Isoenzymes
  • Protein Subunits
  • Receptor, Parathyroid Hormone, Type 1
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Cyclic AMP
  • Type C Phospholipases
  • Phospholipase C beta
  • Adenylyl Cyclases
  • Calcium