Energy balance is maintained by a complex homeostatic system involving some signaling pathways and "nutrient sensors" in multiple tissues and organs. Any defect associated with the pathways can lead to metabolic disorders including obesity, type 2 diabetes, and the metabolic syndrome. The 5'-adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) appear to play a significant role in the intermediary metabolism of these diseases. AMPK is involved in the fundamental regulation of energy balance at the whole body level by responding to hormonal and nutrient signals in the central nervous system and peripheral tissues that modulate food intake and energy expenditure. Mammalian target of rapamycin (mTOR),is one of the downstream targets of AMPK functions as an intracellular nutrient sensor to control protein synthesis, cell growth, and metabolism. Recent research demonstrated the possible interplay between mTOR and AMPK signaling pathways. In this review, we will present current knowledge of AMPK and mTOR pathways in regulating energy balance and demonstrate the convergence between these two pathways.

Transient receptor potential canonical (TRPC) channels are Ca2؉ -permeable nonselective cation channels implicated in diverse physiological functions, including smooth muscle contractility and synaptic transmission. However, lack of potent selective pharmacological inhibitors for TRPC channels has limited delineation of the roles of these channels in physiological systems. Here we report the identification and characterization of ML204 as a novel, potent, and selective TRPC4 channel inhibitor. A high throughput fluorescent screen of 305,000 compounds of the Molecular Libraries Small Molecule Repository was performed for inhibitors that blocked intracellular Ca 2؉ rise in response to stimulation of mouse TRPC4␤ by -opioid receptors. ML204 inhibited TRPC4␤-mediated intracellular Ca 2؉ rise with an IC 50 value of 0.96 M and exhibited 19-fold selectivity against muscarinic receptor-coupled TRPC6 channel activation. In wholecell patch clamp recordings, ML204 blocked TRPC4␤ currents activated through either -opioid receptor stimulation or intracellular dialysis of guanosine 5-3-O-(thio)triphosphate (GTP␥S), suggesting a direct interaction of ML204 with TRPC4 channels rather than any interference with the signal transduction pathways. Selectivity studies showed no appreciable block by 10 -20 M ML204 of TRPV1, TRPV3, TRPA1, and TRPM8, as well as KCNQ2 and native voltage-gated sodium, potassium, and calcium channels in mouse dorsal root ganglion neurons. In isolated guinea pig ileal myocytes, ML204 blocked muscarinic cation currents activated by bath application of carbachol or intracellular infusion of GTP␥S, demonstrating its effectiveness on native TRPC4 currents. Therefore, ML204 represents an excellent novel tool for investigation of TRPC4 channel function and may facilitate the development of therapeutics targeted to TRPC4.

SUMMARY mTor kinase is involved in cell growth, proliferation, and differentiation. The roles of mTor activators, Rheb1 and Rheb2, have not been established in vivo. Here, we report that Rheb1, but not Rheb2, is critical for embryonic survival and mTORC1 signaling. Embryonic deletion of Rheb1 in neural progenitor cells abolishes mTORC1 signaling in developing brain and increases mTORC2 signaling. Remarkably, embryonic and early postnatal brain development appears grossly normal in these Rheb1f/f, Nes-cre mice with the notable exception of deficits of myelination. Conditional expression of Rheb1 transgene in neural progenitors increases mTORC1 activity and promotes myelination in the brain. In addition, the Rheb1 transgene rescues mTORC1 signaling and hypomyelination in the Rheb1f/f, Nes-cre mice. Our study demonstrates that Rheb1 is essential for mTORC1 signaling and myelination in the brain, and suggests that mTORC1 signaling plays a role in selective cellular adaptations, rather than general cellular viability.