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J Biol Chem, Vol. 273, Issue 28, 17469-17476, July 10, 1998
From the Department of Pharmacology, University of Washington,
Seattle, Washington 98195, the § Department of Psychiatry
and Behavioral Sciences, University of Washington, Seattle, Washington
98195 and Veterans Affairs Medical Center,
Seattle, Washington 98108
The neurotransmitter serotonin
(5-hydroxytryptamine, 5-HT) plays an important regulatory
role in developing and adult nervous systems. With the exception of the
5-HT3 receptor, all of the cloned serotonin receptors
belong to the G protein-coupled receptor superfamily. Subtypes
5-HT6 and 5-HT7 couple to stimulation of adenylyl cyclases through Gs and display high affinities
for antipsychotic and antidepressant drugs. In the brain, mRNA for
5-HT6 is found at high levels in the hippocampus, striatum,
and nucleus accumbens. 5-HT7 mRNA is most abundant in
the hippocampus, neocortex, and hypothalamus. To better understand how
serotonin might control cAMP levels in the brain, we coexpressed
5-HT6 or 5-HT7A receptors with specific
isoforms of adenylyl cyclase in HEK 293 cells. The 5-HT6
receptor functioned as a typical Gs-coupled receptor in that it stimulated AC5, a Gs-sensitive adenylyl cyclase,
but not AC1 or AC8, calmodulin (CaM)-stimulated adenylyl cyclases that are not activated by Gs-coupled receptors in
vivo. Surprisingly, serotonin activation of 5-HT7A
stimulated AC1 and AC8 by increasing intracellular Ca2+.
5-HT also increased intracellular Ca2+ in primary neuron
cultures. These data define a novel mechanism for the regulation of
intracellular cAMP by serotonin.
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