期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 1, 期 1, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3000071
关键词
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资金
- Howard Hughes Medical Institute Funding Source: Medline
- NHLBI NIH HHS [R01 HL016037-37, R01 HL016037, R01 HL070631, HL70631, HL16037] Funding Source: Medline
- NICHD NIH HHS [K12 HD043446, HD043446] Funding Source: Medline
- NIDDK NIH HHS [T32 DK007012, DK55524, R56 DK055524, R01 DK064353, R01 DK055524, DK64353] Funding Source: Medline
About 40% of the therapeutic agents in use today exert their effects through seven-transmembrane receptors (7TMRs). When activated by ligands, these receptors trigger two pathways that independently transduce signals to the cell: one through heterotrimeric GTP-binding proteins (G proteins) and one through beta-arrestins; so-called biased agonists can selectively activate these distinct pathways. Here, we investigate selective activation of these pathways through the use of a biased agonist for the type 1 parathyroid hormone (PTH)-PTH-related protein receptor (PTH1R), (D-Trp(12), Tyr(34))-PTH(7-34) (PTH-beta arr), which activates beta-arrestin but not classic G protein signaling. In mice, PTH-beta arr induces anabolic bone formation, as does the nonselective agonist PTH (1-34), which activates both mechanisms. In beta-arrestin2-null mice, the increase in bone mineral density evoked by PTH(1-34) is attenuated and that stimulated by PTH-beta arr is ablated. The beta-arrestin2-dependent pathway contributes primarily to trabecular bone formation and does not stimulate bone resorption. These results show that a biased agonist selective for the beta-arrestin pathway can elicit a response in vivo distinct from that elicited by nonselective agonists. Ligands with these properties may form the basis for improved 7TMR-directed pharmacologic agents with enhanced therapeutic specificity.
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