Ligand‐specific differential regulation of 5‐hydroxytryptamine receptors: functional selectivity in serotonergic signaling

Functional selectivity at a seven transmembrane 5-hydroxytryptamine (5-HT) receptor. Three intracellular effector pathways (E1–E3) are coupled to the receptor, and different ligands (L1–L3) activate these pathways to different extents, leading to alterations in rank orders of efficacy when the three pathways are simultaneously compared. In this schematic example, rank orders of efficacy are L3 > L2 > L1 at E1, L2 > L1 > L3 at E2, and L1 > L3 > L2 at E3. According to classical receptor theory, rank orders of efficacy should be constant across the three effector pathways. Thus, altered rank orders of efficacy provide evidence for ligand-induced differential effector activation, i.e., functional selectivity of signaling through the receptor. (Adapted with permission from Ref 5. Copyright 1998 The American Society for Pharmacology and Experimental Therapeutics)

Regulatory mechanisms underlying functional selectivity at 5-HT receptors. This simplified schematic depicts some of the mechanisms through which functional selectivity at 5-HT receptors is controlled, as discussed in the present review. Note that the absence or presence of connections between the individual molecular components does not imply actual regulatory pathways. For example, ERK is upstream of PLA2 in some cells, but this is not shown here. [1] Ligands can selectively activate different G protein subtypes coupled to a single receptor, [2] which can lead to differential regulation of intracellular signaling cascades. [3] Adaptor proteins such as arrestins bind to intracellular receptor domains, e.g., the third intracellular loop of 5-HT2A, modulating signaling in a ligand-dependent manner. [4] RNA editing causes amino acid alterations in the second intracellular loop of 5-HT2C, effects of which include changes in functional selectivity patterns of ligand-dependent and constitutive signaling. [5] Receptor internalization is an important regulatory mechanism that can be recruited in a ligand-specific manner; in the case of 5-HT2A, various antagonists (like agonists) cause internalization, even though (unlike the agonists) they do not activate signaling. Mechanisms of receptor desensitization and resensitization, which are also subject to functional selectivity (e.g., as revealed by the use of inverse agonists at 5-HT2C), have been omitted for clarity.