Rapid 1α,25(OH)2D3 membrane-mediated activation of Ca2+/calmodulin-dependent protein kinase II in growth plate chondrocytes requires Pdia3, PLAA and caveolae

The growth plates are cartilage tissues found at both ends of developing bones, and vital proliferation and differentiation of growth plate chondrocytes are primarily responsible for bone growth. C-type natriuretic peptide (CNP) stimulates bone growth by activating natriuretic peptide receptor 2 (NPR2) which is equipped with guanylate cyclase on the cytoplasmic side, but its signaling pathway is unclear in growth plate chondrocytes. We previously reported that transient receptor potential melastatin-like 7 (TRPM7) channels mediate intermissive Ca2+ influx in growth plate chondrocytes, leading to activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) for promoting bone growth. In this report, we provide experimental evidence indicating a functional link between CNP and TRPM7 channels. Our pharmacological data suggest that CNP-28 evoked NPR2 activation elevates cellular cGMP content and stimulates big-conductance Ca2+-dependent K+ (BK) channels as a substrate for cGMP-dependent protein kinase (PKG). BK channel-induced hyperpolarization likely enhances the driving force of TRPM7-mediated Ca2+ entry and seems to accordingly activate CaMKII. Indeed, ex vivo organ culture analysis indicates that CNP-facilitated bone growth is abolished by chondrocyte-specific Trpm7 gene ablation. The defined CNP signaling pathway, the NPR2-PKG-BK channel-TRPM7 channel-CaMKII axis, likely pinpoints promising target proteins for developing new therapeutic treatments for divergent growth disorders.

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Faculty Opinions recommendation of Transgenic calmodulin-dependent protein kinase II activation: dose-dependent effects on synaptic plasticity, learning, and memory.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1007983.100156 ◽

2002 ◽

Author(s):

Karl-Peter Giese

Keyword(s):

Synaptic Plasticity ◽

Protein Kinase ◽

Learning And Memory ◽

Dependent Protein Kinase ◽

Protein Kinase Ii ◽

Dependent Protein ◽

Dose Dependent

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Faculty Opinions recommendation of Oxidized Ca(2+)/calmodulin-dependent protein kinase II triggers atrial fibrillation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718106753.793484777 ◽

2013 ◽

Author(s):

Céline Fiset ◽

Nabil El Khoury

Keyword(s):

Atrial Fibrillation ◽

Protein Kinase ◽

Dependent Protein Kinase ◽

Protein Kinase Ii ◽

Dependent Protein

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Faculty Opinions recommendation of Calcium/Calmodulin-Dependent Protein Kinase II and Eukaryotic Elongation Factor 2 Kinase Pathways Mediate the Antidepressant Action of Ketamine.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732611803.793552068 ◽

2018 ◽

Author(s):

Alan Frazer ◽

Flavia Carreno

Keyword(s):

Protein Kinase ◽

Elongation Factor ◽

Dependent Protein Kinase ◽

Calcium Calmodulin Dependent ◽

Elongation Factor 2 ◽

Eukaryotic Elongation Factor 2 ◽

Eukaryotic Elongation Factor ◽

Protein Kinase Ii ◽

Dependent Protein ◽

Antidepressant Action

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Scutellarin Mitigates Cancer-Induced Bone Pain by Suppressing CaMKII/CREB Pathway in Rat Models

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.17:249-253 ◽

2019 ◽

Vol 17 (3) ◽

pp. 249-253

Author(s):

Liu Chenglong ◽

Liu Haihua ◽

Zhang Fei ◽

Zheng Jie ◽

Wei Fang

Keyword(s):

Protein Kinase ◽

Bone Pain ◽

Binding Protein ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Dependent Protein Kinase ◽

Response Element ◽

Protein Kinase Ii ◽

Element Binding Protein ◽

Dependent Protein

Cancer-induced bone pain is a severe and complex pain caused by metastases to bone in cancer patients. The aim of this study was to investigate the analgesic effect of scutellarin on cancer-induced bone pain in rat models by intrathecal injection of Walker 256 carcinoma cells. Mechanical allodynia was determined by paw withdrawal threshold in response to mechanical stimulus, and thermal hyperalgesia was indicated by paw withdrawal latency in response to noxious thermal stimulus. The paw withdrawal threshold and paw withdrawal latencies were significantly decreased after inoculation of tumor cells, whereas administration of scutellarin significantly attenuated tumor cell inoculation-induced mechanical and heat hyperalgesia. Tumor cell inoculation-induced tumor growth was also significantly abrogated by scutellarin. Ca2+/calmodulin-dependent protein kinase II is a multifunctional kinase with up-regulated activity in bone pain models. The activation of Ca2+/calmodulin-dependent protein kinase II triggers phosphorylation of cAMP-response element binding protein. Scutellarin significantly reduced the expression of phosphorylated-Ca2+/calmodulin-dependent protein kinase II and phosphorylated-cAMP-response element binding protein in cancer-induced bone pain rats. Collectively, our study demonstrated that scutellarin attenuated tumor cell inoculation-induced bone pain by down-regulating the expression of phosphorylated-Ca2+/calmodulin-dependent protein kinase II and phosphorylated-cAMP-response element binding protein. The suppressive effect of scutellarin on phosphorylated-Ca2+/calmodulin-dependent protein kinase II/phosphorylated-cAMP-response element binding protein activation may serve as a novel therapeutic strategy for CIBP management.

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