Four 5‐Hydroxytryptamine₇ (5‐HT₇) Receptor Isoforms in Human and Rat Produced by Alternative Splicing: Species Differences Due to Altered Intron‐Exon Organization

Abstract

The serotonin (5-HT) 5-HT7 receptor subtype is thought to mediate a number of physiological effects in mammalian brain and periphery. Previous studies suggested that alternative splicing might contribute to 5-HT7 receptor diversity as well. We now report that alternative splicing in human and rat tissues produces four 5-HT7 receptor isoforms that differ in their predicted C-terminal intracellular tails. Human and rat partial 5-HT7 cDNAs and intronic sequences were identified and compared. In rat tissues, three 5-HT7 isoforms, here called 5~HT7iai,5 HT7(b), and 5-HT7101, are found. Rat 5HT71a1 [448-amino acid (aa)] and 5-HT7(b) (435-aa) forms arise from alternative splice donor sites. A third new isoform found in rat, 5-HTJ(C) (470-aa), results from a retained exon cassette. Three 5-HT7 mRNA isoforms were also identified in human tissues, where only one isoform was previously described. Two human isoforms represent 5-HT71~1and 5-HT7(b) forms (445-and 432-aa), but the third form does not correspond to 5-HT7101. Instead, it constitutes a distinct isoform, 5-HT7(d) (479-aa), resulting from retention of a separate exon cassette. 5-HT7(d) transcripts are not present in rat because the 5-HT71~1-specifyingexon is absent from the rat 5-HT7 gene. A frame-shifting homologue of the rat 5-HT71~1-specifyingexon is present in the human gene but is not used in the human tissues examined. Tissue-specific splicing differences are present in human between brain and spleen. These studies suggest that alternative splicing may contribute to diversity of 5-HT7 receptor action and that the human and rat repertoires of 5-HT7 splice variants are substantially different.

Potential clozapine target sites on peripheral hematopoietic cells and stromal cells of the bone marrow

“…50 The current data confirm and extend on previous pharmacological 26,27 and mRNA expression studies that suggested the existence of multiple muscarinic receptors on blood lymphocytes. 33,63,51,52 While mRNA for m3, m4, and m5 receptors has been reported in mononuclear cells, the additional detection of m3 and m4 mRNA in neutrophils and stromal cells remains a novel finding. Acetylcholine synthesis and release from T-lymphocytes via muscarinic receptors have been documented; 53 however, such stimulation of muscarinic receptors on stromal cells by direct contact through adhesion molecules remains to be defined.…”

“…[60][61][62][63] Primers and conditions used for amplification of the d4 receptor were as previously published. 32 In addition, primers were not designed within known polymorphic coding regions such as for the 5ht2a and 5ht6 receptors.…”

Mouse β3a‐ and β3b‐adrenoceptors expressed in Chinese hamster ovary cells display identical pharmacology but utilize distinct signalling pathways

“…Many GPCRs have isoforms with di ering C-terminal tails. These include the prostaglandin EP3 receptor Hasegawa et al, 1996;Jin et al, 1997;Irie et al, 1993), a 1A -AR (Chang et al, 1998;Hirasawa et al, 1995), serotonin 5HT 4 (Gerald et al, 1995) and 5HT 7 receptors (Heidmann et al, 1997), and the somatostatin SSTR 2 receptor (Vanetti et al, 1993;Schindler et al, 1998). Most splice variants share similar pharmacology, but some show marked di erences in signalling properties.…”

Ras-dependent ERK Activation by the Human Gs-coupled Serotonin Receptors 5-HT4(b) and 5-HT7(a)

“…The 5-HT receptors, each encoded by a separate gene, have been grouped into families called 5-HT 1 to 5-HT 7 , with some of the families containing several members. The human serotonin receptors 5-HT 4 and 5-HT 7 couple to the heterotrimeric G protein G s and exist in multiple splice variants (10,11). Stimulation of these receptors leads to activation of adenylyl cyclase and a rapid increase in the formation of the intracellular second messenger cAMP.…”