Serotonin (5-HT) is a crucial neurotransmitter that regulates various behaviors and mental states. The efficiency of 5-HT synaptic function is linked to mental disorders, and membrane proteins play a critical role in 5-HT synthesis, storage, release, receptor activation, and inactivation. Recent research highlights significant lipid-protein interactions in synaptic 5-HT proteins, affecting synaptic efficacy. The dynamic lipid composition of synaptic membranes suggests that lipid-protein interactions contribute to 5-HT synapse plasticity. This broader protein-lipid model of the 5-HT synapse necessitates a reevaluation of 5-HT's role in mental disorders. The article discusses the proteins involved in 5-HT synthesis, including tryptophan hydroxylase (TPH) and vesicular monoamine transporter (VMT). It also explores the interaction of 5-HT with its receptors, such as 5-HT1A, 5-HT2A, and 5-HT3A receptors, and their functional roles in different brain regions. The lipid landscape at the 5-HT synapse is reviewed, focusing on the roles of cholesterol, phospholipids, and sphingolipids. Cholesterol and phospholipids are essential for receptor function and signaling, while sphingolipids influence receptor binding and signaling through ceramide metabolism. The article further examines the impact of lipid domains, such as lipid rafts, on 5-HT signaling. These microdomains, enriched in cholesterol and sphingolipids, modulate receptor affinity and signaling. Enzymes controlling lipid metabolism, like sphingomyelin synthases (SMS) and neutral sphingomyelinases (NSM), play a crucial role in regulating lipid domains and their functional characteristics. Finally, the article discusses the role of lipids in managing 5-HT signaling, including the interaction of PUFAs and sphingolipids with 5-HT signaling proteins. PUFAs influence lipid raft structures and 5-HT function, while sphingolipids regulate 5-HT1A-R binding and signaling through ceramide metabolism. The article concludes by emphasizing the importance of lipid-protein interactions in 5-HT signaling and their potential implications for mental health and disorders.Serotonin (5-HT) is a crucial neurotransmitter that regulates various behaviors and mental states. The efficiency of 5-HT synaptic function is linked to mental disorders, and membrane proteins play a critical role in 5-HT synthesis, storage, release, receptor activation, and inactivation. Recent research highlights significant lipid-protein interactions in synaptic 5-HT proteins, affecting synaptic efficacy. The dynamic lipid composition of synaptic membranes suggests that lipid-protein interactions contribute to 5-HT synapse plasticity. This broader protein-lipid model of the 5-HT synapse necessitates a reevaluation of 5-HT's role in mental disorders. The article discusses the proteins involved in 5-HT synthesis, including tryptophan hydroxylase (TPH) and vesicular monoamine transporter (VMT). It also explores the interaction of 5-HT with its receptors, such as 5-HT1A, 5-HT2A, and 5-HT3A receptors, and their functional roles in different brain regions. The lipid landscape at the 5-HT synapse is reviewed, focusing on the roles of cholesterol, phospholipids, and sphingolipids. Cholesterol and phospholipids are essential for receptor function and signaling, while sphingolipids influence receptor binding and signaling through ceramide metabolism. The article further examines the impact of lipid domains, such as lipid rafts, on 5-HT signaling. These microdomains, enriched in cholesterol and sphingolipids, modulate receptor affinity and signaling. Enzymes controlling lipid metabolism, like sphingomyelin synthases (SMS) and neutral sphingomyelinases (NSM), play a crucial role in regulating lipid domains and their functional characteristics. Finally, the article discusses the role of lipids in managing 5-HT signaling, including the interaction of PUFAs and sphingolipids with 5-HT signaling proteins. PUFAs influence lipid raft structures and 5-HT function, while sphingolipids regulate 5-HT1A-R binding and signaling through ceramide metabolism. The article concludes by emphasizing the importance of lipid-protein interactions in 5-HT signaling and their potential implications for mental health and disorders.