STIMULATION OF TYPE-1 AND TYPE-8 CA2+ CALMODULIN-SENSITIVE ADENYLYL CYCLASES BY THE G(S)-COUPLED 5-HYDROXYTRYPTAMINE SUBTYPE-5-HT7A RECEPTOR/

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays an im portant regulatory role in developing and adult nervous systems, With the exception of the 5-HT3 receptor, all of the cloned serotonin recep tors belong to the G protein-coupled receptor superfamily, Subtypes 5 HT6 and 5-HT7 couple to stimulation of adenylyl cyclases through G(s) and display high affinities for antipsychotic and antidepressant drugs . In the brain, mRNA for 5-HT6 is found at high levels in the hippocam pus, striatum, and nucleus accumbens, 5-HT7 mRNA is most abundant in t he 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 G(s)-coupled re ceptor in that it stimulated AC5, a G(s)-sensitive adenylyl cyclase, b ut not AC1 or AC8, calmodulin (CaM)-stimulated adenylyl cyclases that are not activated by G(s) coupled receptors in vivo. Surprisingly, ser otonin activation of 5-HT7A stimulated AC1 and AC8 by increasing intra cellular Ca2+. 5-HT also increased intracellular Ca2+ in primary neuro n cultures. These data define a novel mechanism for the regulation of intracellular cAMP by serotonin.