5-hydroxytryptamine receptor 1A and 5-hydroxytryptamine receptor 2B (5-HT1A and 5-HT2B)

The 5-HT1A and 5-HT2B receptors are distinct subtypes of the serotonin receptor family, both classified as G protein-coupled receptors (GPCRs). The 5-HT1A receptor is primarily located in the central nervous system, where it acts as an inhibitory receptor coupled to Gi/o proteins to regulate mood, cognition, and anxiety [1, 4]. In contrast, the 5-HT2B receptor is expressed in the heart, gastrointestinal tract, and brain, and is coupled to Gq/11 proteins, influencing cardiovascular development and smooth muscle contraction [2, 4]. While 5-HT1A is a major therapeutic target for drugs like buspirone and vilazodone used in treating depression and anxiety, 5-HT2B is often considered a safety anti-target [4]. Chronic 5-HT2B agonism is linked to serious adverse effects, most notably cardiac valvulopathy, which involves the pathological thickening of heart valves [3]. This safety concern led to the withdrawal of several drugs, such as fenfluramine, from the market [3]. Many multi-target drugs, including ergot derivatives and certain antipsychotics, interact with both receptors, requiring careful pharmacological profiling to balance efficacy and safety [4]. Understanding the interplay between these receptors is crucial for developing neuropsychiatric medications that avoid cardiovascular toxicity. Monitoring 5-HT2B activity is now a standard part of the safety assessment for any new serotonergic drug candidate [3, 4].

Other names

Serotonin 1A receptorSerotonin 2B receptorHTR1AHTR2B5-HT1AR5-HT2BR

Agonism at 5-HT1A receptors leads to inhibition of adenylyl cyclase and neuronal hyperpolarization, while agonism at 5-HT2B receptors triggers the phospholipase C pathway and intracellular calcium release [1, 2, 4].