Gs Protein‐Coupled Serotonin Receptors: Receptor Isoforms and Functional Differences

Abstract

Three distinct mammalian Gs coupled serotonin receptor genes have been identified, 5-HT4, 5-ht6, and 5-HT7, which produce at least seven different functional receptors through alternative splicing. One of the chief questions facing workers in this area mirrors that confronting the serotonin receptor field as a whole: why so many subtypes? The answer to this question is made more elusive at present by two further considerations. First, there may well be additional Gs coupled receptor subtypes yet to be described. Secondly, although the various isoforms of 5-HT4 and 5-HT7 have been shown to be functional in in vitro assays, it remains to be shown that all isoforms have biological significance. This paper will summarize some of the differences at the molecular and cellular level that are becoming apparent among the 5-HT4, 5-ht6 and 5-HT7 receptor subtypes and their various isoforms. As an example, it will focus on the 5-HT7 system, and describe recent developments in ascribing particular functions to differences due to alternative splicing.

A Hybrid Structural Approach to Analyze Ligand Binding by the Serotonin Type 4 Receptor (5-HT4)

“…Apart from the highly conserved alignment of the toggle switch residues, a key difference in the binding site interactions for GR125487 in 5-HT4R involves W294 7.35 on the back face of the heteroaromatic ring. The bulky aromatic ring of W294 interacts strongly with the heteroaromatic moiety of GR125487 through F275 6 ous studies of bovine rhodopsin using radiolytic footprinting and MS, internal waters near residue side chains buried within the bilayers were shown to mediate side-chain oxidation (13,15). This correlation of water positions and side-chain oxidation was analyzed in the context of footprinting data obtained from experiments with 5-HT4R.…”

“…With the exception of 5-HT3, all other 5-HT receptors are members of the class A family of GPCRs. 5-HT4 receptors (5-HT4Rs), like some of the other family members (5-HT6R and 5-HT7R), are associated with an excitatory G s protein that evokes a cAMP increase upon activation (6). There are four major isoforms of 5-HT4R translated from the same gene by alternate splicing of the C terminus (7).…”

5-Hydroxytryptamine Modulates Migration, Cytokine and Chemokine Release and T-Cell Priming Capacity of Dendritic Cells In Vitro and In Vivo

“…5-HTR 1A interacts with several G proteins, eliciting different responses [5]. 5-HTR 1B and 5-HTR 1D are coupled to formation of inositol phosphates through interaction with pertussis toxin–sensitive G i/o and pertussis toxin–insensitive G q proteins [6].…”

Serotonergic Modulation of Neuronal Activity in the Nucleus Accumbens Following Repeated Methamphetamine Administration in Rats

“…In addition, the mechanism of potentiation of only 5-HT 7 receptor-mediated response among Gs-coupled 5-HT receptors by repeated MAP treatment needs to be elucidated. One possible reason for this phenomenon is that some Gs-coupled 5-HT receptors use different subclasses of secondary messenger systems from others (25,26). In addition, the augmentation of PS by LP-12, one of the 5-HT 7 receptor agonists, was smaller than that by AS 19.…”