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A Docking Site for G Protein ß Subunits on the Parathyroid Hormone 1 Receptor Supports Signaling through Multiple Pathways

Endocrine Unit, Massachusetts General Hospital (M.J.M., P.D.), Boston, Massachusetts 02114; and Department of Pharmacology and Physiology (T.M.B., A.V.S.), University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Address all correspondence and requests for reprints to: Matthew J. Mahon, Endocrine Unit, Massachusetts General Hospital, Wellman 501, 50 Blossom Street, Boston, Massachuesetts 02114. E-mail: mahon{at}helix.mgh.harvard.edu.

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 G_i/o proteins in vitro. All three subunits of the heterotrimer interact with the receptor C-tail. Activation of the heterotrimeric complex with GTPS has no effect on Gß interactions, but markedly disrupts binding of the G_i/o subunits to the receptor tail, suggesting that direct Gß binding indirectly links G subunits to this region of the receptor. Gß subunits alone bind the C-tail with an affinity that is comparable to the heterotrimeric G protein complex. G protein complexes consisting of G_shis₆-ß₁₂ and G_qhis₆-ß₁₂ also interact with the PTH1R tail in vitro. The Gß interaction domain is located on the juxta-membrane region of the tail between amino acids 468 and 491. Mutations that disrupt Gß interactions block PTH signaling via phospholipase Cß/[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 Gß interactions.

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