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Vol. 61, Issue 1, 85-96, January 2002
s- and Gi/o-Proteins
Department of Receptor Pharmacology, Janssen Research Foundation,
B-2340 Beerse, Belgium
This study documents differences in ligand binding and signal
transduction properties between the human (h) 5-hydroxytryptamine (5-HT)4a and h5-HT4b receptor splice variants
stably expressed in human embryonic kidney 293 cells. The fraction of
the [3H]5-HT high-affinity site relative to the whole
receptor population measured with [3H]GR113808 was higher
for the h5-HT4a isoform (around 0.4) than for the
5-HT4b isoform (around 0.2) and was independent of the level of expression. The potency and efficacy of reference compounds tested for the cAMP response differed slightly but significantly between both variants. Most remarkably, 5-methoxytryptamine and prucalopride were found more potent on the 5-HT4b variant,
whereas SDZ-HTF 919 and SB204070 were more potent on the
5-HT4a variant. Guanosine-5'-O-(3-[35S]thio)triphosphate
binding on membranes and cAMP assays in whole cells revealed that only
the h5-HT4b isoform coupled to G
i/o-proteins in addition
to its well-documented Gs coupling. In contrast, the
h5-HT4a receptor coupled only to Gs-proteins, however,
was able to trigger an increase in the intracellular calcium
concentration ([Ca2+]i). The observed
[Ca2+]i increase did not occur through
inositol phosphate formation and was not sensitive to Bordatella
pertussis toxin, forskolin, or 3-isobutyl-1-methylxanthine
(pre)treatment but was due to Ca2+ influx from the
extracellular environment. Interestingly, the Ca2+ pathway
was dependent on high receptor expression levels and was
compound-specific, because benzamide-like compounds triggered two to
three times higher responses than indoleamines. Taken together, these
data provide the first evidence for fine functional differences between
C-terminal splice variants of the h5-HT4 receptor, which may contribute to a better understanding of the functional diversity of
this receptor class.
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