التفاصيل البيبلوغرافية
| العنوان: |
Muscarinic Toxin 7 Signals Via Ca2+/Calmodulin-Dependent Protein Kinase Kinase β to Augment Mitochondrial Function and Prevent Neurodegeneration |
| المؤلفون: |
Saleh, Ali, Sabbir, Mohammad Golam, Aghanoori, Mohamad-Reza, Smith, Darrell R, Roy Chowdhury, Subir K, Tessler, Lori, Brown, Jennifer, Gedarevich, Eva, Kassahun, Markos Z, Frizzi, Katie, Calcutt, Nigel A, Fernyhough, Paul |
| المصدر: |
Molecular Neurobiology, vol 57, iss 6 |
| بيانات النشر: |
eScholarship, University of California |
| سنة النشر: |
2020 |
| المجموعة: |
University of California: eScholarship |
| مصطلحات موضوعية: |
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Clinical Sciences, Neurosciences, Diabetes, Peripheral Neuropathy, Neurodegenerative, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Neurological, Animals, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Diabetes Mellitus, Experimental, Elapid Venoms, Ganglia, Spinal, Mitochondria, Muscarinic Antagonists, Nerve Degeneration, Neuronal Outgrowth, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phosphorylation, Pirenzepine, Rats, Sensory Receptor Cells, Signal Transduction, Antimuscarinic, Bioenergetics |
| الوقت: |
2521 - 2538 |
| الوصف: |
Mitochondrial dysfunction is implicated in a variety of neurodegenerative diseases of the nervous system. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a regulator of mitochondrial function in multiple cell types. In sensory neurons, AMP-activated protein kinase (AMPK) augments PGC-1α activity and this pathway is depressed in diabetes leading to mitochondrial dysfunction and neurodegeneration. Antimuscarinic drugs targeting the muscarinic acetylcholine type 1 receptor (M1R) prevent/reverse neurodegeneration by inducing nerve regeneration in rodent models of diabetes and chemotherapy-induced peripheral neuropathy (CIPN). Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) is an upstream regulator of AMPK activity. We hypothesized that antimuscarinic drugs modulate CaMKKβ to enhance activity of AMPK, and PGC-1α, increase mitochondrial function and thus protect from neurodegeneration. We used the specific M1R antagonist muscarinic toxin 7 (MT7) to manipulate muscarinic signaling in the dorsal root ganglia (DRG) neurons of normal rats or rats with streptozotocin-induced diabetes. DRG neurons treated with MT7 (100nM) or a selective muscarinic antagonist, pirenzepine (1μM), for 24h showed increased neurite outgrowth that was blocked by the CaMKK inhibitor STO-609 (1μM) or short hairpin RNA to CaMKKβ. MT7 enhanced AMPK phosphorylation which was blocked by STO-609 (1μM). PGC-1α reporter activity was augmented up to 2-fold (p < 0.05) by MT7 and blocked by STO-609. Mitochondrial maximal respiration and spare respiratory capacity were elevated after 3h of exposure to MT7 (p < 0.05). Diabetes and CIPN induced a significant (p < 0.05) decrease in corneal nerve density which was corrected by topical delivery of MT7. We reveal a novel M1R-modulated, CaMKKβ-dependent pathway in neurons that represents a therapeutic target to enhance nerve repair in two of the most common forms of peripheral neuropathy. |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
unknown |
| العلاقة: |
qt6kz9k8nh; https://escholarship.org/uc/item/6kz9k8nhTest |
| الإتاحة: |
https://escholarship.org/uc/item/6kz9k8nhTest |
| حقوق: |
public |
| رقم الانضمام: |
edsbas.9025BB3F |
| قاعدة البيانات: |
BASE |
