Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions

The broadly distributed monoaminergic neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) exerts its actions via 14 classes of receptor. With the exception of 5-HT₃ receptors, which gate a cation-permeable ion channel, all 5-HT receptors are coupled to G proteins. The core features of transduction via 5-HT receptors are well established, but much still remains to be learned, in particular, with regard to native populations in the brain. In this article, we survey the current knowledge of cellular signaling at G-protein-coupled 5-HT receptors and focus on several novel (and surprising) insights that have emerged over the past few years. We also highlight several promising directions for future research that should improve the understanding of serotonin signaling and ultimately permit its therapeutic exploitation in the control of central nervous system disorders. In view of the diversity of transduction mechanisms engaged by 5-HT, much of this discussion is relevant to other classes of G-protein-coupled receptors.

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.