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Structure of the Human Serotonin 5‐HT 4 Receptor Gene and Cloning of a Novel 5‐HT 4 Splice Variant
Author(s) -
Bender Eckhard,
Pindon Armelle,
Van Oers Irma,
Zhang YuBin,
Gommeren Walter,
Verhasselt Peter,
Jurzak Mirek,
Leysen Josee,
Luyten Walter
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.740478.x
Subject(s) - splice , alternative splicing , receptor , gene isoform , exon , 5 ht5a receptor , 5 ht receptor , rna splicing , biology , serotonin , gene , gabbr1 , 5 ht7 receptor , g protein coupled receptor , microbiology and biotechnology , genetics , protease activated receptor 2 , rna
Several variants of the serotonin 5‐HT 4 receptor are known to be produced by alternative splicing. To survey the existence and usage of exons in humans, we cloned the human 5‐HT 4 gene. Based on sequence analysis seven C‐terminal variants (a‐g) and one internal splice variant (h) were found. We concentrated in this study on the functional characterization of the novel splice variant h, which leads to the insertion of 14 amino acids into the second extracellular loop of the receptor. The h variant was cloned as a splice combination with the C‐terminal b variant; therefore, we call this receptor 5‐HT 4(hb) . This novel receptor variant was expressed transiently in COS‐7 cells, and its pharmacological profile was compared with those of the previously cloned 5‐HT 4(a) and 5‐HT 4(b) isoforms, with the latter being the primary reference for the h variant. In competition binding experiments using reference 5‐HT 4 ligands, no significant differences were detected. However, the broadly used 5‐HT 4 antagonist GR113808 discriminated functionally among the receptor variants investigated. As expected, it was an antagonist on the 5‐HT 4(a) and 5‐HT 4(b) variant but showed partial agonistic activity on the 5‐HT 4(hb) variant. These data emphasize the importance of variations introduced by splicing for receptor pharmacology and may help in the understanding of conflicting results seen with 5‐HT 4 ligands in different model systems.