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The mammalian brain is one of the organs with the highest energy demands, and mitochondria are key determinants of its functions. Here we show that the type-1 cannabinoid receptor (CB₁) is present at the membranes of mouse neuronal mitochondria (mtCB₁), where it directly controls cellular respiration and energy production. Through activation of mtCB₁ receptors, exogenous cannabinoids and in situ endocannabinoids decreased cyclic AMP concentration, protein kinase A activity, complex I enzymatic activity and respiration in neuronal mitochondria. In addition, intracellular CB₁ receptors and mitochondrial mechanisms contributed to endocannabinoid-dependent depolarization-induced suppression of inhibition in the hippocampus. Thus, mtCB₁ receptors directly modulate neuronal energy metabolism, revealing a new mechanism of action of G protein–coupled receptor signaling in the brain.