The article "Role of Endogenous Cannabinoids in Synaptic Signaling" by Freund, Katona, and Piomelli reviews the role of endogenous cannabinoids, particularly anandamide and 2-arachidonoylglycerol (2-AG), in synaptic signaling. The authors discuss the biosynthesis, release, and degradation of these compounds, as well as their distribution and functional roles in the brain. Key points include: 1. **Biosynthesis**: Anandamide is synthesized from arachidonic acid and ethanolamine through the actions of phospholipase D and N-acyltransferase. 2-AG is formed through phospholipase C-mediated hydrolysis of membrane phospholipids, followed by diacylglycerol lipase activity. 2. **Release**: Both anandamide and 2-AG can be generated and released from neurons without vesicular secretion, likely through passive diffusion or facilitated by lipid-binding proteins. 3. **Transport and Degradation**: Anandamide and 2-AG are transported into nerve endings and glia via carrier-mediated processes. Anandamide is rapidly hydrolyzed by fatty acid amide hydrolase (FAAH), which also acts as a reverse enzyme to synthesize anandamide from arachidonic acid and ethanolamine. 4. **CB1 Receptor Distribution**: The authors highlight the presynaptic localization of CB1 receptors on axon terminals, which is crucial for the regulation of neurotransmitter release. This localization is supported by anatomical, physiological, and pharmacological evidence. 5. **Physiological Roles**: Endocannabinoids play a significant role in controlling neurotransmitter release, particularly at GABAergic and glutamatergic synapses. They are involved in retrograde signaling, which is essential for short-term synaptic plasticity such as depolarization-induced suppression of inhibition (DSI) and excitation (DSE). 6. **Conclusion**: The review emphasizes the importance of understanding the physiological functions of endogenous cannabinoids in normal and pathological brain activity. Future research will focus on developing pharmacological agents that target the cascade of anandamide and 2-AG formation, release, uptake, and degradation to explore their potential therapeutic applications. The article provides a comprehensive overview of the current understanding of endocannabinoids and their role in synaptic signaling, highlighting the need for further research to uncover their full potential in both normal and pathological conditions.The article "Role of Endogenous Cannabinoids in Synaptic Signaling" by Freund, Katona, and Piomelli reviews the role of endogenous cannabinoids, particularly anandamide and 2-arachidonoylglycerol (2-AG), in synaptic signaling. The authors discuss the biosynthesis, release, and degradation of these compounds, as well as their distribution and functional roles in the brain. Key points include: 1. **Biosynthesis**: Anandamide is synthesized from arachidonic acid and ethanolamine through the actions of phospholipase D and N-acyltransferase. 2-AG is formed through phospholipase C-mediated hydrolysis of membrane phospholipids, followed by diacylglycerol lipase activity. 2. **Release**: Both anandamide and 2-AG can be generated and released from neurons without vesicular secretion, likely through passive diffusion or facilitated by lipid-binding proteins. 3. **Transport and Degradation**: Anandamide and 2-AG are transported into nerve endings and glia via carrier-mediated processes. Anandamide is rapidly hydrolyzed by fatty acid amide hydrolase (FAAH), which also acts as a reverse enzyme to synthesize anandamide from arachidonic acid and ethanolamine. 4. **CB1 Receptor Distribution**: The authors highlight the presynaptic localization of CB1 receptors on axon terminals, which is crucial for the regulation of neurotransmitter release. This localization is supported by anatomical, physiological, and pharmacological evidence. 5. **Physiological Roles**: Endocannabinoids play a significant role in controlling neurotransmitter release, particularly at GABAergic and glutamatergic synapses. They are involved in retrograde signaling, which is essential for short-term synaptic plasticity such as depolarization-induced suppression of inhibition (DSI) and excitation (DSE). 6. **Conclusion**: The review emphasizes the importance of understanding the physiological functions of endogenous cannabinoids in normal and pathological brain activity. Future research will focus on developing pharmacological agents that target the cascade of anandamide and 2-AG formation, release, uptake, and degradation to explore their potential therapeutic applications. The article provides a comprehensive overview of the current understanding of endocannabinoids and their role in synaptic signaling, highlighting the need for further research to uncover their full potential in both normal and pathological conditions.