Should pharmacologists care about alternative splicing? IUPHAR Review 4

Abstract

Alternative splicing of mRNAs occurs in the majority of human genes, and most differential splicing results in different protein isoforms with possibly different functional properties. However, there are many reported splicing variations that may be quite rare, and not all combinatorially possible variants of a given gene are expressed at significant levels. Genes of interest to pharmacologists are frequently expressed at such low levels that they are not adequately represented in genome-wide studies of transcription. In single-gene studies, data are commonly available on the relative abundance and functional significance of individual alternatively spliced exons, but there are rarely data that quantitate the relative abundance of full-length transcripts and define which combinations of exons are significant. A number of criteria for judging the significance of splice variants and suggestions for their nomenclature are discussed.

Keywords: 5-HT4 receptor; CaV1.2; CaV3.1; PAC1 receptor; alternative splicing; splice variant nomenclature.

Figure 1

Types of splice variants. Exons are represented by coloured boxes and introns by dashed lines. Solid lines represent sequences spliced out by alternative splicing choices, and the resulting alternatively spliced products are shown to the right of the arrows.

Figure 2

Human Ca_V1.2 gene structure and splice variants. Diagram of alternative splicing of Ca_V1.2 transcripts adapted from Tang (2004). Exons are numbered based on the numbering of Soldatov (1994), with more recently discovered exons added as exons 1a, 8a, 9*, 10* and 45*, and are mapped onto the protein structure that they encode. Note that exon 8a precedes exon 8 in the genome and exon 1a precedes exon 1, which is also called exon 1b in rat. Exons 3, 7, 15, 17, 32, 41 and 45* use alternative splice acceptors or splice donors, resulting in length variations of 4, 12, 73, 9 or 12, 6, 57 and 187 nucleotides respectively.

Figure 3

Human 5-HT₄ receptor splice variants. Constitutively spliced coding exons are numbered. Alternatively spliced coding exons are labelled h, s, i, bc, d, gef and a. The g2 exon is an exception, as it is untranslated, but the g2 transcript encodes the same isoform as the g variant. Exons and spacing between them are not to scale.