CROSS-TALK BETWEEN 5-HYDROXYTRYPTAMINE RECEPTORS IN A SEROTONERGIC CELL-LINE - INVOLVEMENT OF ARACHIDONIC-ACID METABOLISM

The study of signaling cascades and of functional interactions between 5-hydroxytryptamine (5-HT) receptor pathways with heterogenous brain cell populations remains an arduous task. We took advantage of a serot onergic cell Line to elucidate cross-talks between 5-HT receptors and to demonstrate the involvement of two 5-HT2 receptor subtypes in the r egulation of 5-HT1B/1D function. The inducible 1C11 cell line has the unique property of acquiring within 4 days a complete serotonergic phe notype (1C11 cells), including three 5-HT receptors. 5-HT1B/1D and 5- HT2B receptors are expressed since day 2 of the serotonergic different iation while 5-HT2A receptors are induced at day 4. We first establish ed that 5-HT2B receptors are coupled with the phospholipase A2 (PLA2)- mediated release of arachidonic acid (AA) and that the activation of 5 -HT2B receptors in 1C11d2 cells inhibits the 5-HT1B/1D receptor funct ion via a cyclooxygenase dependent AA metabolite. At day 4, this 5-HT2 B-mediated inhibition of the 5-HT1B/1D function can be blocked upon co ncomitant 5-HT2A activation although a 5-HT2A/PLA2 positive coupling w as evidenced. This suggests the existence in 1C11d4 cells of pathway( s) for 5-HT2A receptors, distinct from PLC and PLA2. Finally, this stu dy reveals the antagonistic roles of 5-HT2A and 5-HT2B receptors in re gulating the function of 5-HT1B/1D, a receptor involved in neuropsychi atric disorders and migraine pathogenesis.