Editorial Material
Biochemistry & Molecular Biology
Jean-Pierre Vilardaga, Ieva Sutkeviciute, Karina A. Pena
Summary: The study demonstrates the significant impact of localized cAMP production on cellular functions, particularly in phospho-responses, as revealed through phospho-proteomic analysis.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Review
Cell Biology
Karina A. Pena
Summary: The canonical model for GPCR activation assumes that activation occurs only at the cell surface and is turned off by receptor internalization. However, recent research has shown that some internalized GPCRs can continue to signal from endosomes, which has physiological implications.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Review
Physiology
Patricia P. Centeno, Lenah S. Binmahfouz, Khaleda Alghamdi, Donald T. Ward
Summary: The calcium-sensing receptor (CaR) functions as a sensor and controller of extracellular calcium concentration, and it is also sensitive to and modulated by other ions and small ligands besides calcium. Emerging evidence suggests that extracellular phosphate can act as a non-competitive antagonist of the CaR, modulating parathyroid hormone secretion and integrating mineral homeostasis. Intracellular phosphorylation of certain CaR residues can also inhibit its responsiveness, reducing CaR activity both extracellularly (via association with arginine) and intracellularly (via covalent phosphorylation).
FRONTIERS IN PHYSIOLOGY
(2023)
Article
Agriculture, Dairy & Animal Science
J. R. B. Freitag, M. R. Wilkens, A. S. Muscher-Banse, K. Gerstner, N. Schnepel, P. R. Torgerson, A. Liesegang
Summary: The study investigated the basic effects of DCAD on different calcium supplies in a sheep model. Results showed that the lowDCAD group had lower urine pH, higher urinary calcium excretion, higher ionized calcium in the blood, and higher serum calcium concentrations.
JOURNAL OF DAIRY SCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Peng Zhou, Hongxu Yang, Mian Zhang, Jinqiang Liu, Jia Yu, Shibin Yu, Qian Liu, Yuejiao Zhang, Mianjiao Xie, Xiaojie Xu, Jiguang Liu, Meiqing Wang
Summary: This study aimed to investigate the role of calcium-sensing receptor (CaSR) and parathyroid hormone-related peptide (PTHrP87-139) in the proliferation of superficial zone cells in mandibular condylar cartilage. Results showed that CaSR promoted the expression of PTHrP, leading to increased proliferation and early differentiation of superficial zone cells. Deletion of CaSR or PTHrP genes suppressed cartilage thickness and cell proliferation. Therefore, CaSR can be a therapeutic target for promoting PTHrP production in superficial zone cartilage.
Article
Biochemistry & Molecular Biology
Peng Zhou, Hongxu Yang, Mian Zhang, Jinqiang Liu, Jia Yu, Shibin Yu, Qian Liu, Yuejiao Zhang, Mianjiao Xie, Xiaojie Xu, Jiguang Liu, Meiqing Wang
Summary: This study aimed to investigate the relationship between calcium-sensing receptor (CaSR) and parathyroid hormone-related peptide nuclear localization sequence (PTHrP(87-139)), and their role in the proliferation of superficial zone cells in mandibular condylar cartilage. The findings showed that CaSR and PTHrP expression were stimulated by fluid flow shear stress (FFSS), leading to increased proliferation of superficial zone cells. Furthermore, CaSR acted as an upstream regulator of PTHrP and modulated the proliferation of superficial zone cells through the activation of PTHrP nuclear localization sequence.
Article
Endocrinology & Metabolism
Christoph Klenk, Leif Hommers, Martin J. Lohse
Summary: This study reveals that the extracellular domain of PTH1R is cleaved by metalloproteinases, leading to impaired stability of the receptor. The cleavage site is located in the first loop of the extracellular domain. A receptor mutant resistant to proteolytic cleavage showed reduced signaling to G(s) and increased activation of G(q).
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Pharmacology & Pharmacy
Moritaka Goto, Go Nishimura, Hirofumi Sato, Yu Yamaguchi, Nobutaka Morimoto, Hiroyuki Hashimoto, Naoki Takahashi
Summary: Upacicalcet is a non-peptide calcimimetic agent that shows potential as an alternative treatment for secondary hyperparathyroidism in chronic kidney disease. It activates the calcium-sensing receptor in a calcium concentration-dependent manner, without exhibiting agonistic activity at sub-physiological levels. Upacicalcet effectively reduces parathyroid hormone and serum calcium levels in rats, without affecting gastric emptying. Compared to other calcimimetics, it has good pharmacological properties and a lower risk of hypocalcemia and gastrointestinal complications.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Kazuhiro Kobayashi, Kouki Kawakami, Tsukasa Kusakizako, Hirotake Miyauchi, Atsuhiro Tomita, Kan Kobayashi, Wataru Shihoya, Keitaro Yamashita, Tomohiro Nishizawa, Hideaki E. Kato, Asuka Inoue, Osamu Nureki
Summary: This study reports the cryoelectron microscopic structures of the human PTH1R-Gs complex in the presence of endogenous parathyroid hormone and PTH-related peptide, revealing distinct ligand-receptor interactions and signaling durations induced by these two ligands.
Article
Cell Biology
Mengrong Li, Yiqiong Bao, Ran Xu, Miaomiao Li, Lili Xi, Jingjing Guo
Summary: The identification and development of non-peptide allosteric modulators for PTH1R have gained attention. It has been found that a negative allosteric modulator (NAM) inhibits the activation of PTH1R, but the mechanism is unclear. Molecular dynamics simulations and analytical approaches reveal that NAM destabilizes the PTH1R-PTH-spep/qpep complexes, weakens PTH/peps-PTH1R binding, and reduces intra- and inter-molecular couplings in PTH1R. Compared with positive allosteric effects induced by extracellular Ca2+, the negative allosteric regulator significantly reduces the correlation between PTH and G-protein binding sites. These findings contribute to the development of new therapeutics for diseases caused by PTH1R abnormal activation.
Article
Biochemistry & Molecular Biology
Mengrong Li, Yiqiong Bao, Ran Xu, Honggui La, Jingjing Guo
Summary: This study used molecular dynamics simulations to investigate the binding of parathyroid hormone receptor to G-protein, as well as how calcium ions allosterically engage in the process. The results showed that calcium ions stabilize the conformation of the complex and promote interaction between the receptor and G-protein, revealing insights into possible allosteric signaling pathways.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Ieva Sutkeviciute, Ji Young Lee, Alex D. White, Christian Santa Maria, Karina A. Pena, Sofya Savransky, Pemra Doruker, Hongchun Li, Saifei Lei, Burak Kaynak, Chialing Tu, Lisa J. Clark, Subramaniam Sanker, Thomas J. Gardella, Wenhan Chang, Ivet Bahar, Jean-Pierre Vilardaga
Summary: By using molecular dynamics simulations and elastic network model-based methods, the study identified a key mechanical site that modulates the collective dynamics of PTHR and successfully identified selective small molecules with strong negative allosteric properties for PTHR signaling. This computational pipeline provides a way to detect precise druggable sites and identify allosteric modulators for GPCRs, expediting the discovery of small molecules as novel therapeutic candidates.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Urology & Nephrology
Alia Hassan, Yael E. E. Pollak, Rachel Kilav-Levin, Justin Silver, Nir London, Morris Nechama, Iddo Z. Z. Ben-Dov, Tally Naveh-Many
Summary: This study reveals that kidney failure leads to the loss of Pin1 activity in the parathyroid glands, resulting in increased production of PTH. Pin1 and KSRP phosphorylation, as well as the Pin1-KSRP-PTH mRNA axis, play important roles in secondary hyperparathyroidism.
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2022)
Article
Biochemistry & Molecular Biology
Bhushan C. Dhandare, Mohd Ashraf Rather, B. P. Bhosale, Ravindra Pawar, Praveen Kumar Guttula, A. U. Pagarkar
Summary: This study analyzed the structural features, homology modeling, and molecular docking of Labeo rohita growth hormone receptor (GHR) protein. The results showed the binding energy values and molecular interactions of the ligands Melengestrol and Riboflavin with the GHR protein. Molecular dynamics simulation revealed that the Riboflavin-GHR protein complex was superior to the Melengestrol-GHR protein complex.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Review
Endocrinology & Metabolism
Salvatore Minisola, Andrew Arnold, Zhanna Belaya, Maria Luisa Brandi, Bart L. Clarke, Fadil M. Hannan, Lorenz C. Hofbauer, Karl L. Insogna, Andre Lacroix, Uri Liberman, Andrea Palermo, Jessica Pepe, Rene Rizzoli, Robert Wermers, Rajesh Thakker
Summary: This narrative review provides an overview of the epidemiology, pathophysiology, and genetics of primary hyperparathyroidism (PHPT). PHPT primarily affects postmenopausal women, but its prevalence and incidence vary globally. Parathyroid hormone plays a key role in regulating calcium homeostasis, and the pathophysiological basis of PHPT involves abnormal proliferation of parathyroid cells and reduced expression of calcium-sensing receptors. The severity of skeletal disease in PHPT depends on the degree of dysregulated bone remodeling. Genetic factors contribute to approximately 10% of PHPT cases, including multiple endocrine neoplasia syndromes, hyperparathyroidism jaw-tumor syndrome, and isolated endocrinopathies.
JOURNAL OF BONE AND MINERAL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Ali Mehri, Karim Mahnam, Hajar Sirous, Mahmoud Aghaei, Leila Rafiei, Mahboubeh Rostami
Summary: One potential approach for tumor therapy is inhibiting the binding between MDM2 and p53 to reactivate p53 in tumor cells. In this study, Monastrol derivatives were designed as MDM2 inhibitors and evaluated for their cytotoxicity on cancer cells. Compound 5d showed the best inhibitory results in silico and in vitro experiments. These findings suggest that Monastrol derivatives have the potential to be candidates for MDM2 inhibition.
CHEMICAL BIOLOGY & DRUG DESIGN
(2024)