Modified 5-HT3A receptor function by co-expression of alternatively spliced human 5-HT3A receptor isoforms.
Serotonin (5-HT) exerts fast excitatory responses by activation of 5-HT3 receptors, irrespective of whether they are homomerically composed of 5-HT3A subunits or heteromerically assembled of 5-HT3A and 5-HT3B subunits. Here we describe a short, truncated (h5-HT3AT) and a long (h5-HT3AL) splice variant of the human 5-HT3A (hS-HT3A) receptor subunit. The deduced protein of the short isoform consists of 238 amino acids (aa) with a single transmembrane domain (M1). Compared to the known 5-HT3A receptor, the long isoform contains 32 additional aa in the extracellular loop between M2 and M3. Both splice variants are co-expressed together with the 5-HT3A subunit in the amygdala and hippocampus, whereas in the placenta only the short variant is co-expressed. Both splice variants, when expressed in transfected human embryonic kidney (HEK) 293 cells, are not able to form functional homomeric receptors, but modify 5-HT response at heteromeric h5-HT3A receptors. Co-expression of the short variant considerably decelerates the desensitization of the 5-HT3 receptor; thus, heteromeric assemblies of h5-HT3A and the h5-HT3AT subunit exhibit 5-HT-induced cation fluxes which are much larger than those of homomeric hS-HT3A receptors. In contrast, heteromeric complexes containing the h5-HT3AL subunit display reduced cation fluxes. In conclusion, the splice variants increase the functional diversity of 5-HT3 receptors.
Brüss
M
M
Institut für Pharmakologie und Toxikologie, Universität Bonn, Germany. m.bruess@uni-bonn.de
Barann
M
M
Hayer-Zillgen
M
M
Eucker
T
T
Göthert
M
M
Bönisch
H
H
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000032:analysis / Q000502:physiology; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D044406:Receptors, Serotonin, 5-HT3; D014407:Tumor Cells, Cultured
D020033:Protein Isoforms; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3