Bohinc Brittany N, Gesty-Palmer Diane
Department of Medicine, Division of Endocrinology and Metabolism, Duke University Medical, Center, Durham, NC 27710, USA.
Endocr Metab Immune Disord Drug Targets. 2011 Jun;11(2):112-9. doi: 10.2174/187153011795564151.
Parathyroid hormone (PTH) is a principle regulator of bone and calcium metabolism and PTH analogs hold great promise as a therapy for metabolic bone diseases such as osteoporosis. PTH acts principally through the type IPTH/PTH-related peptide receptor (PTH1R), a G protein coupled receptor (GPCR). GPCRs are a family of seven transmembrane cell surface receptors that share conserved structural, functional, and regulatory properties. Recent studies demonstrate that the complex metabolic effects induced by PTH1R stimulation are not entirely a consequence of conventional GPCR signaling. β-arrestins, in addition to their GPCR desensitizing actions, also serve as multifunctional scaffolding proteins linking the PTH1R to signaling molecules independent of the classic G protein coupled second messenger-dependent pathways. In vitro, D-Trp(12),Tyr(34)-bPTH(7-34) (PTH-βarr), a β-arrestin selective biased agonist for the PTH1R, antagonizes receptor-G protein coupling but activates arrestin-dependent signaling. In vivo, intermittent administration of, PTH-βarr to mice, induces anabolic bone formation, completely independent of classic G protein-coupled signaling mechanisms. While both PTH-βarr and the conventional agonist PTH(1-34) stimulate anabolic bone formation in mice, unlike PTH(1-34), which activates G protein coupling, PTH-βarr does not induce hypercalcemia or increase markers of bone resorption. This newly recognized ability of β-arrestins to serve as signal transducers for the PTH1R represents an innovative paradigm of receptor signaling which can be targeted to induce a subset of physiologic responses in bone. Exploitation of β-arrestin biased agonism may offer therapeutic benefit for the treatment of metabolic bone diseases such as osteoporosis.
甲状旁腺激素（PTH）是骨骼和钙代谢的主要调节因子，PTH类似物作为治疗骨质疏松症等代谢性骨病的疗法具有巨大潜力。PTH主要通过I型PTH/ PTH相关肽受体（PTH1R）发挥作用，PTH1R是一种G蛋白偶联受体（GPCR）。GPCR是一类七跨膜细胞表面受体家族，具有保守的结构、功能和调节特性。最近的研究表明，PTH1R刺激所诱导的复杂代谢效应并不完全是传统GPCR信号传导的结果。β-抑制蛋白除了具有GPCR脱敏作用外，还作为多功能支架蛋白，将PTH1R与信号分子连接起来，独立于经典的G蛋白偶联第二信使依赖性途径。在体外，D-Trp(12),Tyr(34)-bPTH(7-34)（PTH-βarr），一种针对PTH1R的β-抑制蛋白选择性偏向激动剂，可拮抗受体-G蛋白偶联，但激活抑制蛋白依赖性信号传导。在体内，向小鼠间歇性给药PTH-βarr可诱导合成代谢性骨形成，完全独立于经典的G蛋白偶联信号传导机制。虽然PTH-βarr和传统激动剂PTH(1-34)都能刺激小鼠的合成代谢性骨形成，但与激活G蛋白偶联的PTH(1-34)不同，PTH-βarr不会诱导高钙血症或增加骨吸收标志物。β-抑制蛋白作为PTH1R信号转导分子的这一新发现能力代表了一种受体信号传导的创新模式，可用于诱导骨骼中的一部分生理反应。利用β-抑制蛋白偏向激动作用可能为治疗骨质疏松症等代谢性骨病提供治疗益处。
