The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays an important regulatory role in developing and adult nervous systems. With the exception of the 5-HT 3 receptor, all of the cloned serotonin receptors belong to the G protein-coupled receptor superfamily. Subtypes 5-HT 6 and 5-HT 7 couple to stimulation of adenylyl cyclases through G s and display high affinities for antipsychotic and antidepressant drugs. In the brain, mRNA for 5-HT 6 is found at high levels in the hippocampus, striatum, and nucleus accumbens. 5-HT 7 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-HT 6 or 5-HT 7A receptors with specific isoforms of adenylyl cyclase in HEK 293 cells. The 5-HT 6 receptor functioned as a typical G s -coupled receptor in that it stimulated AC5, a G s -sensitive adenylyl cyclase, but not AC1 or AC8, calmodulin (CaM)-stimulated adenylyl cyclases that are not activated by G s -coupled receptors in vivo. Surprisingly, serotonin activation of 5-HT 7A stimulated AC1 and AC8 by increasing intracellular Ca 2؉ . 5-HT also increased intracellular Ca 2؉ in primary neuron cultures. These data define a novel mechanism for the regulation of intracellular cAMP by serotonin.
Serotonin (5-hydroxytryptamine, 5-HT)1 is a ubiquitous neurotransmitter that elicits a variety of physiological effects peripherally and centrally (1-3). A growing family of plasma membrane receptors bind 5-HT and mediate its cellular effects (4). All of the 5-HT receptors except 5-HT 3 belong to the superfamily of G protein-coupled receptors. The recently cloned 5-HT 6 (5, 6) and 5-HT 7 (7-10) receptors activate adenylyl cyclase(s) through the heterotrimeric G protein G s , and expression of these receptors in cultured cells couples serotonin to increases in cAMP (6,8). 5-HT 6 and 5-HT 7 display high affinities for antipsychotic and antidepressant drugs including clozapine, amoxapine, and amitryptiline (5-8), suggesting a role for these receptors in affective function. In the brain, the 5-HT 6 receptor is most highly expressed in the hippocampus, nucleus accumbens, striatum, and limbic regions, and the 5-HT 7 receptor is found in the hypothalamus, hippocampus, and cortex. The distribution of these receptors in brain is consistent with the hypothesis that they play a role in mood and affect (8,(11)(12)(13). In addition, the expression of the 5-HT 7 receptor in the suprachiasmatic nucleus (SCN) and the ability of serotonin and cAMP to advance the mammalian circadian rhythm indicates that 5-HT 7 plays an important role in circadian physiology (10, 14, 15). 5-HT 7 receptors are also expressed in glial cells (16,17) and at lower levels in peripheral tissues including the spleen, intestine, and vascular smooth muscle (7-9, 18).Many psychotherapeutic agents modulate the cAMP signaling pathway (19) and perturbation of this signal transduction system may contribute to some affective disorders. To date, nine distinct cDNA clones for mammalian...