Dual Regulation of the Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Signaling by Protein Kinase C and β-Arrestins

Castro, Marián; Dicker, Frank; Vilardaga, Jean-Pierre; Krasel, Cornelius; Bernhardt, Manfred; Lohse, Martin J.

doi:10.1210/en.2002-220232

Cited by 44 publications

(33 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4C shows that simultaneous addition of PTH(1-34) TMR (3 M) and [Aib 1,3 , M]PTH(1-14) (10 M) eliminated the second phase, whereas the first phase remained mostly unchanged (k obs ϭ 2.78 Ϯ 0.15 s Ϫ1 and a corresponding amplitude of A ϭ 6.5 Ϯ 0.7%, n ϭ 6). The subsequent removal of [Aib 1,3 , M]PTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) restored the full response seen with PTH(1-34) TMR alone (Fig. 4D).…”

Section: Two-mentioning

confidence: 87%

“…[Aib 1,3 ,M]PTH (1-14) (peptide sequence Aib-V-Aib-E-I-Q-L-M-H-Q-Har-A-K-W-NH 2 ) was kindly provided by T. Gardella (Massachusetts General Hospital and Harvard Medical School, Boston); [Aib 1,3 ,M] refers to the combined modifications of Aib 1,3 , Gln-10, Har 11 , Ala-12, and Trp-14 on human PTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), where Aib is the ␣-amino-isobutyric acid and Har is homoarginine (8).…”

Section: Methodsmentioning

confidence: 99%

“…Extensive studies have demonstrated that [Aib 1,3 , M]PTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) and other PTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) analogs (8,(19)(20)(21) mainly, if not exclusively, bind to the PTHR J-domain in contrast to PTH(1-34), which binds to both receptor's N-and J-domains (22). When [Aib 1,3 , M]PTH (1-14) is bound, it prevents PTH analogs from occupying their binding site at the J-domain of the receptor (8,18).…”

Section: Two-mentioning

confidence: 99%

“…When [Aib 1,3 , M]PTH (1-14) is bound, it prevents PTH analogs from occupying their binding site at the J-domain of the receptor (8,18). In the next experiment, we examined whether the specific association of [Aib 1,3 , M]PTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) to the receptor J-domain is able to differentiate the two kinetically distinct phases were directly proportional to the agonist concentration, whereas k obs values for the second step (k obs slow , ‚) followed an hyperbolic dependence on agonist concentration and reach a constant value k obs Ϸ0.8 s Ϫ1 . Results for rate constants for PTHR activation (F) originate from our previous study (7).…”

Section: Two-mentioning

confidence: 99%

See 3 more Smart Citations

Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism

Castro

Nikolaev²,

Palm³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

169

150

View full text Add to dashboard Cite

FRET ͉ G protein-coupled receptor ͉ time-resolved signaling ͉ real-time binding ͉ ligand-receptor interaction P arathyroid hormone (PTH) is an 84-aa peptide that regulates concentrations of calcium and phosphate in blood and is of paramount importance in renal and bone metabolism (1). PTH is secreted from the parathyroid glands in response to hypocalcemia and elicits its physiological effects in kidney and bone through the activation of a G protein-coupled receptor, the PTH͞PTH-related receptor (PTHR) (2). In response to PTH this receptor leads to activation of adenylyl cyclases (via G s protein) that in turn increase the intracellular second messenger cAMP, which activates the protein kinase A (PKA)-signaling pathway. PTHR also activates the phospholipase C͞protein kinase C-signaling pathways (via G q protein), although less efficiently than the PKA-signaling pathway (3). PTH(1-34), a synthetic PTH fragment with the first 34 aa of PTH that holds the same pharmacological properties in regard to the regulation of calcium homeostasis as the full-length hormone (4), has recently become a drug (the generic name is teriparatide) approved by the U.S. Food and Drug Administration to treat osteoporosis (5, 6). The resolution of the mode of interaction of PTH(1-34) to its receptor is critical for understanding the mechanism of action of the hormone and for further progressing in drug development to treat osteoporosis.We recently showed that activation of PTHR by binding of PTH(1-34) proceeds by fast conformational changes (time constant Ϸ 1 s) as the receptor switches from a resting to an active state (7). To further our understanding on the PTHR interaction process we resolved the temporal events of PTH(1-34) binding to PTHR in living cells. We measured kinetics of association by FRET between tetramethyl-rhodamine (TMR) (the acceptor fluorophore) conjugated to PTH(1-34) and GFP (the donor fluorophore) inserted into the N-terminal domain of the receptor (Fig. 1A). This study reports the analysis of these kinetics and reveals a two-step process for PTH(1-34) binding, where the first phase mirrored agonist binding to the receptor N-domain with a fast association rate and the second phase reflected association to the J-domain, exhibiting much slower kinetics but temporally coupled to receptor activation. Materials and MethodsPeptides. Human PTH(1-34) was purchased from Bachem, and the radioligand [ 125

show abstract

Section: Two-mentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Two-mentioning

confidence: 99%

Section: Two-mentioning

confidence: 99%

See 2 more Smart Citations

Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism

Castro

Nikolaev²,

Palm³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

169

150

View full text Add to dashboard Cite

show abstract

“…Intermittent administration of PTH(1-34) has been shown to stimulate bone formation (21,22) and is used for treating osteoporosis (23)(24)(25). The function of PTH(1-34) on osteoblastlineage cells for bone formation is mediated through PTHR1, a heterotrimeric G protein-coupled receptor (26) that primarily mediates PTH signaling and then transmits it through protein kinase A (PKA) and PKC intracellular signaling pathways (27,28). The 1-34 amino acid fragments of both PTH and PTHrP contain the functional subdomains for PTHR1 signaling (29,30).…”

Section: Discussionmentioning

confidence: 99%

Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats

Chang¹,

Chang²,

Hung³

et al. 2009

Arthritis & Rheumatism

100

120

View full text Add to dashboard Cite

Objective. Parathyroid hormone 1-34 (PTH[1-34]), a parathyroid hormone analog, shares the same receptor, PTH receptor 1, with parathyroid hormone-related peptide (PTHrP). This study was undertaken to address the hypothesis that PTH(1-34) inhibits terminal differentiation of articular chondrocytes and in turn suppresses the progression of osteoarthritis (OA).Methods. We studied the effect of PTH(1-34) on human articular chondrocytes with azacytidine (azaC)-induced terminal differentiation in vitro and on papaininduced OA in the knee joints of rats. In the in vitro study, we measured the levels of messenger RNA for SOX9, aggrecan, type II collagen, type X collagen, alkaline phosphatase (AP), Indian hedgehog (IHH), Bcl-2, and Bax by real-time polymerase chain reaction, levels of glycosaminoglycan (GAG) by dimethylmethylene blue assay, and rate of apoptosis by TUNEL staining. In the in vivo study, we evaluated the histologic changes in GAG, type II collagen, type X collagen, and chondrocyte apoptosis in the articular cartilage of rat knees.Results. AzaC induced terminal differentiation of human chondrocytes, including down-regulation of aggrecan, type II collagen, and GAG and up-regulation of type X collagen, alkaline phosphatase, and IHH. Apoptosis was reversed by 3-10 days of treatment with 10 nM PTH(1-34). SOX9 expression was not changed by either azaC or PTH(1-34) treatment. Bcl-2 and Bax were up-regulated on day 10 and day 14, respectively, after azaC induction of terminal differentiation, but PTH(1-34) treatment did not reverse this effect. Furthermore, PTH(1-34) treatment reversed papaininduced OA changes (decreasing GAG and type II collagen, and increasing type X collagen and chondrocyte apoptosis) in the knee joints of rats.Conclusion. Our findings indicate that PTH(1-34) inhibits the terminal differentiation of human articular chondrocytes in vitro and inhibits progression of OA in rats in vivo, and may be used to treat OA.

show abstract

PTH and Vitamin D

Khundmiri

Murray

Lederer

2016

Comprehensive Physiology

234

158

View full text Add to dashboard Cite

PTH and Vitamin D are two major regulators of mineral metabolism. They play critical roles in the maintenance of calcium and phosphate homeostasis as well as the development and maintenance of bone health. PTH and Vitamin D form a tightly controlled feedback cycle, PTH being a major stimulator of vitamin D synthesis in the kidney while vitamin D exerts negative feedback on PTH secretion. The major function of PTH and major physiologic regulator is circulating ionized calcium. The effects of PTH on gut, kidney, and bone serve to maintain serum calcium within a tight range. PTH has a reciprocal effect on phosphate metabolism. In contrast, vitamin D has a stimulatory effect on both calcium and phosphate homeostasis, playing a key role in providing adequate mineral for normal bone formation. Both hormones act in concert with the more recently discovered FGF23 and klotho, hormones involved predominantly in phosphate metabolism, which also participate in this closely knit feedback circuit. Of great interest are recent studies demonstrating effects of both PTH and vitamin D on the cardiovascular system. Hyperparathyroidism and vitamin D deficiency have been implicated in a variety of cardiovascular disorders including hypertension, atherosclerosis, vascular calcification, and kidney failure. Both hormones have direct effects on the endothelium, heart, and other vascular structures. How these effects of PTH and vitamin D interface with the regulation of bone formation are the subject of intense investigation.

show abstract

Dual Regulation of the Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Signaling by Protein Kinase C and β-Arrestins

Cited by 44 publications

References 45 publications

Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism

Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism

Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats

PTH and Vitamin D

Contact Info

Product

Resources

About