Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimer’s disease.

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“Despite efforts to understand the mechanism of neuronal cell death, finding effective therapies for neurodegenerative diseases is still a challenge. Cognitive deficits are often associated with neurodegenerative diseases.

Remarkably, in the absence of consensus biomarkers, diagnosis of diseases such as Alzheimer’s still relies on cognitive tests. Unfortunately, all efforts to translate findings in animal models to the patients have been unsuccessful. Alzheimer’s disease may be addressed from two different points of view, neuroprotection or cognitive enhancement.

Based on recent data, the mammalian target of rapamycin (mTOR) pathway arises as a versatile player whose modulation may impact on mechanisms of both neuroprotection and cognition. Whereas direct targeting of mTOR does not seem to constitute a convenient approach in drug discovery, its indirect modulation by other signaling pathways seems promising.

In fact, G-protein-coupled receptors (GPCRs) remain the most common ‘druggable’ targets and as such pharmacological manipulation of GPCRs with selective ligands may modulate phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and mTOR signaling pathways.

Thus, GPCRs become important targets for potential drug treatments in different neurodegenerative disorders including, but not limited to, Alzheimer’s disease. GPCR-mediated modulation of mTOR may take advantage of different GPRCs coupled to different G-dependent and G-independent signal transduction routes, of functional selectivity and/or of biased agonism. Signals mediated by GPCRs may act as coincidence detectors to achieve different benefits in different stages of the neurodegenerative disease.”

https://www.ncbi.nlm.nih.gov/pubmed/28189739

Cannabinoid Receptor 1 and Acute Resistance Exercise – In vivo and In vitro Studies in Human Skeletal Muscle.

“This study aimed to determine whether cannabinoid receptor 1 (CB1) is involved in mammalian target of rapamycin (mTOR) signaling and skeletal muscle protein synthesis…

Our results indicate that RE down-regulates CB1 expression. Inhibition of CB1 signaling increases skeletal muscle anabolic signaling down-stream of mTOR and protein synthesis through ERK1/2.

Our study may provide base for the development of CB1-blocking drugs to treat or prevent muscle wasting.”

http://www.ncbi.nlm.nih.gov/pubmed/25796352