Identification of a human 5-HT6 receptor variant produced by alternative splicing

The complexity of the 5-hydroxytryptamine (5-HT) (serotonin) receptor famil y has been increased by the findings that isoforms or splice variants exist for subtypes such as the 5-HT2B, 5-HT2c, 5-HT4 and 5-HT7 subtypes. Further molecular biological studies in our laboratory have demonstrated that a sp lice variant of the 5-HT6 receptor exists in the human brain. Experiments p erformed using a degenerate PCR approach from human caudate cDNA revealed a 5-HT6 receptor clone with a 289 bp deletion of the region coding for trans membrane IV through the third intracellular loop. This deletion produces a frameshift creating a downstream stop codon which results in a truncated pr otein containing 10 unique amino acids at its carboxyl end. The variant tra nscript occurs as a result of alternative splicing using an upstream donor site and the acceptor site from the first intron in the 5-HT6 receptor gene . The splicing pattern seen for this transcript was not detected in rat or mouse whole brain cDNA by PCR due to the lack of a consensus 5' donor site. Coexpression of the variant 5-HT6 transcript and the full length 5-HT6 tra nscript was observed in caudate and substantia nigra but not in hippocampus , cortex, cerebellum and thalamus. Transient transfection of a 5-HT6 varian t construct into Cos-7 cells demonstrated that a truncated receptor was tra nslocated to the membrane but appeared nonfunctional. (C) 1999 Elsevier Sci ence B.V. All rights reserved.