Abstract
G-protein-coupled receptors (GPCRs), which are encoded by >300 genes in the human genome, are by far the largest class of targets for modern drugs. These macromolecules display inherent adaptability of function, which is partly due to the production of different forms of the receptor protein. These are commonly called ‘isoforms’ or ‘splice variants’ denoting the molecular process of their production/assembly. Not all GPCRs are expressed as splice variants, but certain subclasses of 5–HT receptors are for example, the 5–HT4 and 5–HT7 receptors. There are at least 11 human 5–HT4 and three h5–HT7 receptor splice variants. This review describestheir discoveries, nomenclature and structures. The discovery that particular splice variants are tissue specific (or prominent) has highlighted their potential as future drug targets. In particular, this review examines the functional relevance of different 5–HT4 and 5–HT7 receptor splice variants. Examples are given to illustrate that splice variants have differential modulatory influences on signalling processes. Differences in agonist potency and efficacies and also differences in desensitisation rates to 5–HT occur with both 5–HT4 and 5–HT7 receptor splice variants. The known and candidate signalling systems that allow for splice variant specific responses include GPCR interacting proteins (GIPs) and GPCR receptor kinases (GRKs) which are examined.Finally, the relevance of 5–HT receptor splice variants to clinical medicine and to the pharmaceutical industry is discussed.
Highlights
G-protein-coupled receptors (GPCRs) are by far the largest class of targets for modern drugs
Are they expressed in specific tissues? Do they modulate signalling processes in different fashions? If so, could they act as potential therapeutic targets? Here we will discuss these questions in relation to serotonin receptor splice variants with an emphasis on the distribution of 5-HT4 and 5-HT7 receptor splice variants and their potential as therapeutic targets
While the 5HT4(e) receptor splice variant co-localised with CIPP which is a scaffolding protein and importantly this was not seen with the 5HT4(b) receptor splice variant which does not contain a PDZ ligand [42]. These exciting results do indicate that the PDZ ligand domains of 5-HT4 or 5-HT7 receptor splice variants contribute to the receptor localisation and suggest that rates of receptor desensitisation may vary with the splice variant expressed
Summary
G-protein-coupled receptors (GPCRs) are by far the largest class of targets for modern drugs. These macromolecules are encoded by >300 genes in the human genome. Different products can be generated from a single GPCR gene by the combination of alternative forms of particular exons. This process is referred to as ‘alternative splicing’ and translated products are called ‘splice variants’ or more commonly ‘isoforms’ (see Fig. 1). Over 70% of multi-exon genes expressed in humans are alternatively spliced to form various splice variants and the proteins involved in cellular communication are common amongst examples [41]. Of the serotonin (5-hydroxytryptamine, 5-HT) receptors, the 5-HT4 and 5-HT7 receptors in particular are noteworthy for the production of several splice variants [40]
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