Amino-Terminal Parathyroid Hormone Fragment Analogs Containing α,α-di-alkyl Amino Acids at Positions 1 and 3

Shimizu, Naoto; Dean, Thomas R.; Khatri, Ashok; Gardella, Thomas J.

doi:10.1359/jbmr.040914

Cited by 34 publications

(31 citation statements)

References 50 publications

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“…In contrast, the agonist profile of MPTH(1-28) is similar to that of PTH(1-34), suggesting that N-terminal AA substitutions increasing a-helicity of the N-terminal domain (Okazaki et al, 2008) help maintain agonist activity of PTH(1-28) analogs. However, introduction of the same AA substitutions into more extensive C-terminal truncated peptides helps predominately to maintain agonist activity to stimulate G s -signaling, as reported by others (Shimizu et al, 2001(Shimizu et al, , 2004Caporale et al, 2009Caporale et al, , 2010Neerup et al, 2011). The structural basis for the greater capacity of PTH(1-28), [Gly 1 ,Arg 19 ]PTH(1-28), ZP2307, and MPTH(1-14) to stimulate receptor internalization is unclear but may be a result of C-terminal AAs present in PTH(1-31) providing a restraint on receptor internalization.…”

Section: Discussionmentioning

confidence: 70%

Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor–Mediated Signaling Pathways

Cupp¹,

Nayak²,

Adem³

et al. 2013

J Pharmacol Exp Ther

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Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), acting through the osteoblast PTH1 receptor (PTH1R), play important roles in bone remodeling. Intermittent administration of PTH(1-34) (teriparatide) leads to bone formation, whereas continuous administration paradoxically leads to bone resorption. Activation of PTH1R promotes regulation of multiple signaling pathways, including G s /cAMP/protein kinase A, G q /calcium/protein kinase C, b-arrestin recruitment, and extracellular signal-related kinase (ERK)1/2 phosphorylation, as well as receptor internalization, but their role in promoting anabolic and catabolic actions of PTH(1-34) are unclear. In the present investigation, a collection of PTH(1-34) and PTHrP(1-34) peptide analogs were evaluated in orthogonal human PTH1R (hPTH1R) functional assays capturing G s -and G q -signaling, b-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization to further define the patterns of PTH1R signaling that they stimulate and further establish peptide domains contributing to agonist activity. Results indicate that both Nand C-terminal domains of PTH and PTHrP are critical for activation of signaling pathways. However, modifications of both regions lead to more substantial decreases in agonist potency and efficacy to stimulate G q -signaling, b-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization than to stimulate G s -signaling. The substantial contribution of the peptide C-terminal domain in activation of hPTH1R signaling suggests a role in positioning of the peptide N-terminal region into the receptor J-domain. Several PTH and PTHrP peptides evaluated in this study promote different patterns of biased agonist signaling and may serve as useful tools to further elucidate therapeutically relevant PTH1R signaling in osteoblasts. With a better understanding of therapeutically relevant signaling, novel biased peptides with desired signaling could be designed for safer and more effective treatment of osteoporosis.

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Section: Discussionmentioning

confidence: 70%

Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor–Mediated Signaling Pathways

Cupp¹,

Nayak²,

Adem³

et al. 2013

J Pharmacol Exp Ther

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“…The N-terminal modifications, which typically include conformationally constraining amino acid analogs, such as a-amino isobutyric acid substituted at positions 1 and/or 3, also conferred detectable cAMP-signaling potency to the otherwise inactive PTH(1-11) peptide (Shimizu et al, 2001a(Shimizu et al, ,b, 2004, along with at least some a-helicity (Barazza et al, 2005;Fiori et al, 2007;Caporale et al, 2009aCaporale et al, ,b, 2010Cupp et al, 2013b). It thus may be that for the native ligand, the N-terminal domain becomes structurally more organized as an a-helix upon binding to the receptor (Shimizu et al, 2001b(Shimizu et al, , 2004, as has been suggested for other peptide ligands that bind to a family B GPCR (Parthier et al, 2009).…”

Section: B Parathyroid Hormone-related Proteinmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

2015

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“…To explore the possibility that the slow step of binding related to receptor activation we used [Aib 1,3 , M]PTH(1-14) (see Materials and Methods), a conformationally constrained PTH(1-14)-derived agonist with increased ␣-helicity and similar binding and signaling properties as PTH(1-34) (8,18). 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).…”

Section: Two-mentioning

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). In the next experiment, we examined whether the specific association of [Aib 1,3 , M]PTH (1)(2)(3)(4)(5)(6)(7)…”

Section: Two-mentioning

confidence: 99%

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.

168

150

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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

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Amino-Terminal Parathyroid Hormone Fragment Analogs Containing α,α-di-alkyl Amino Acids at Positions 1 and 3

Cited by 34 publications

References 50 publications

Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor–Mediated Signaling Pathways

Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor–Mediated Signaling Pathways

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

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

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