Diverse signalling by 5-hydroxytryptamine (5-HT) receptors

Fourteen different receptor subtypes might be regarded as a diversity that is sufficient to accommodate the wide-ranging physiological roles of 5-hydroxytryptamine (5-HT). However, it is becoming clear that, for 5-HT as for other neurotransmitters, the concept of a receptor as a gatekeeper for a specific cellular process or event is too restrictive. Multiple receptor-mediated biochemical cascades can be activated in cells in response to an agonist by a number of mechanisms. Whereas it is well established that different agonists do not necessarily elicit the same magnitude of response, they probably also select between various possible signal transduction pathways. Receptor signalling may be diverse via a single receptor subtype as a consequence of specific agonist-receptor-G protein interactions. 5-HT receptors are even more heterogeneous when one considers that the amino acid sequence of these receptor subtypes may vary from individual to individual, and that there is an increasing number of receptor isoforms due to alternative splicing and RNA editing of 5-HT receptor transcripts. Activation, in particular constitutive, agonist-independent activation, of some of these receptor isoforms has been reported to be altered. This implies that ligands with similar binding affinities may display different pharmacological properties (partial agonist, antagonist, or inverse agonist) versus these receptor isoforms, depending on their activation state. Therefore, intervention with receptor ligands to modify hampered neurotransmission pathways is a difficult task, and one needs to consider the growing evidence of diversity in G protein-coupled receptor signalling.