Trends in Pharmacological Sciences
ReviewSignaling at G-protein-coupled serotonin receptors: recent advances and future research directions
Introduction
The phylogenetically ancient monoamine 5-hydroxytryptamine (5-HT), which is found in organisms as diverse as barnacles, bumble-bees, bears and bower-birds, fulfills a broad and species-specific role in the control of many vital functions.
In humans, 5-HT is derived from dietary tryptophan, which is transformed into 5-HT in the brain mainly by the neuron-specific ‘2’ isoform of tryptophan hydroxylase (Figure 1). Its actions are terminated by transporter-mediated reuptake into neurons, leading to catabolism by monoamine oxidase (Figure 1). 5-HT functions via 14 classes of receptor, which are all present (and differentially distributed) in the central nervous system (CNS), including the frontal cortex, hippocampus, amygdala, striatum, hypothalamus and dorsal horn 1, 2, 3, 4. Through actions at these multiple classes of receptor, 5-HT controls almost any core CNS function one might care to mention, such as mood, cognition, sleep, pain, motor function and endocrine secretion. Correspondingly, a disruption of serotonergic transmission is implicated in the pathogenesis of depression, anxiety, schizophrenia and chronic pain, and many agents used for their treatment function, at least partially, via serotonergic mechanisms 1, 2.
An improvement of serotonergic therapeutics necessitates a better understanding both of the functional significance of multiple classes of 5-HT receptor and of their actions at the cellular level. Indeed, although the basic characteristics of serotonin signaling are now familiar, most studies have been performed on recombinant receptors individually expressed in non-neuronal cell lines 3, 4, 5 (Box 1 and Figure 1). As emphasized later, we are still woefully ignorant of how cerebral 5-HT receptors operate in real life: alone and in interaction with other sites, under physiological and pathological conditions, and in response to therapy.
The term ‘signaling’ is, in a sense, open ended. Ultimately, signaling is translated into changes of mood and behavior, whereas alterations in electrical activity and gene expression are relevant endpoints at the cellular level. However, integration of such information would render this review inordinately diffuse. Thus, the present article focuses on (i) the influence of G-protein-coupled 5-HT receptors upon soluble second messengers and (ii) the remarkable diversity of serotonergic signaling in the CNS. Several recently discovered insights into the cellular actions of 5-HT are highlighted, together with other novel themes likely to animate research in this field over the coming years.
Section snippets
New signaling pathways recruited by G-protein-coupled serotonin receptors
The principal signaling mechanisms recruited by 5-HT receptors are outlined in Box 1 and Figure 1, and the influence of post-transcriptional modification of 5-HT receptors upon transduction is summarized in Box 2. However, there are many variations on the core themes of serotonin transduction (Table 1), and the following recent observations are of special interest.
5-HT6 receptors are well known to recruit Gαs and adenylyl cyclase (AC), but their cellular pharmacology was recently enlivened by
Concretizing recent developments
One important avenue for future research will be the confirmation of these recent developments in serotonin signaling, their further characterization in the brain and clarification of their functional and therapeutic significance. The following topics are also likely to attract particular interest over the coming years.
Signaling at 5-HT receptors in the brain: return to the future
It is important to distinguish the plethora of data from solitary recombinant 5-HT receptors expressed in cell lines from rare observations on native brain populations in their
Concluding remarks
Signaling via G-protein-coupled 5-HT receptors is extraordinarily diverse, and the recent developments discussed here underline its complexity. There is an urgent need to further our understanding of serotonergic transduction in discrete cerebral regions, in defined classes of neurons, in response to therapy and under physiological and pathological conditions. Also, as accentuated here, signaling in non-neuronal cells should not be neglected. Finally, the functional significance of specific
Acknowledgements
We thank Benjamin Di Cara for assistance with graphics.
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