Muscarinic Toxin 7 Signals Via Ca 2+ /Calmodulin-Dependent Protein Kinase Kinase β to Augment Mitochondrial Function and Prevent Neurodegeneration

• Published in: Molecular neurobiology 2020-06, Vol.57 (6), p.2521
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism; Diabetes Mellitus, Experimental - metabolism; Elapid Venoms - pharmacology; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Mitochondria - drug effects; Mitochondria - metabolism; Muscarinic Antagonists - pharmacology; Nerve Degeneration - metabolism; Neuronal Outgrowth - drug effects; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Phosphorylation - drug effects; Pirenzepine - pharmacology; Rats; Sensory Receptor Cells - drug effects; Sensory Receptor Cells - metabolism; Signal Transduction - drug effects
• ISSN: 1559-1182
• DOI: 10.1007/s12035-020-01900-x

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 (M R) prevent/reverse neurodegeneration by inducing nerve regeneration in rodent models of diabetes and chemotherapy-induced peripheral neuropathy (CIPN). Ca /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 M R 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 (100 nM) or a selective muscarinic antagonist, pirenzepine (1 μM), for 24 h showed increased neurite outgrowth that was blocked by the CaMKK inhibitor STO-609 (1 μM) or short hairpin RNA to CaMKKβ. MT7 enhanced AMPK phosphorylation which was blocked by STO-609 (1 μM). PGC-1α reporter activity was augmented up to 2-fold (p