Serotonergic signaling: Multiple effectors and pleiotropic effects

Abstract

Serotonin (5-HT) is a neurotransmitter which exerts both central and peripheral control on numerous physiological functions such as sleep/wake cycle, thermoregulation, food intake, nociception, locomotion, sexual behavior, gastrointestinal motility, blood coagulation, and cardiovascular homeostasis. These multiple effects are mediated by a family of serotonin receptors which comprises at least 13 distinct G-protein-coupled receptors (GPCRs) of the A type and a combination of ligand-gated cation channel heteropentameric receptors of the conserved 5-HT3 Cys-loop type. Many of these receptors are targets of pharmaceutical drugs justifying the wide interest to elucidate their functioning. Over the past decades, substantial investigations have led to the current understanding of the complex signal transduction mechanisms which these receptors initiate. The idea of a unique coupling of a receptor to a linear pathway has evolved into a multiplicity of alternative bifurcations and feedback mechanisms. The emerging signaling model includes the capacity of 5-HT receptors GPCR superfamily to couple and initiate transduction through several G proteins depending on the tissue and/or the presence of interacting proteins. In turn, these G proteins may activate many effectors. On the other hand, the complexity increases further with the capacity of 5-HT receptors to transduce signals through G-protein-independent pathways. These multiple couplings often participate in the control of gene transcription, thereby resulting in 5-HT-mediated long-term (neuroplastic) adaptive functional changes. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.