Serotonin 5-HT(1C) receptor-mediated second messenger production and interactions in choroid plexus

The serotonin 5-HT{dollar}sb{lcub}rm 1C{rcub}{dollar} receptor of choroid plexus has been shown to be coupled to phosphoinositide (PI) turnover. A structure-activity analysis was performed for three groups of serotonergic compounds using this second messenger system. A rank order of efficacy of PI turnover is indolealkylamines {dollar}>{dollar} phenylpiperazines {dollar}>{dollar} ergolines. Substitutions at the 5 and 7 positions of indolealkylamines altered compound affinity and efficacy of PI turnover. 2 position bromination of Lysergic acid diethylamide (LSD) abolished the PI response produced by LSD. Receptor structures interacting with indole 5 and 7 positions and with the 2 position of LSD are important determinants of affinity and efficacy of 5-HT{dollar}sb{lcub}rm 1C{rcub}{dollar} receptors.; We demonstrate that the 5-HT{dollar}sb{lcub}rm 1C{rcub}{dollar} receptor couples to another second messenger system: cyclic guanosine 3{dollar}spprime{dollar},5{dollar}spprime{dollar}-monophosphate (cGMP) production. The pharmacology of the cGMP response is nearly identical to that for PI turnover and indicates that the 5-HT{dollar}sb{lcub}rm 1C{rcub}{dollar} receptor produces both second messengers concurrently. cGMP production is dependent on extracellular calcium. Lipoxygenase metabolites of arachidonic acid are required to observe cGMP formation as inhibition with BW755C blocks cGMP formation. Phospholipase A{dollar}sb2{dollar} is involved in arachidonate liberation as its inhibition with p-bromophenacylbromide reduces cGMP production.; In several systems cyclic nucleotide second messengers have been shown to inhibit PI turnover. High 5-HT concentrations lead to elevations in cyclic GMP (see above) and cyclic AMP in choroid plexus. Enhancement of cAMP levels with dibutyrylcAMP and isoproterenol minimally affected, while agents which increase cGMP levels (dibutyrylcGMP, sodium nitroprusside, sodium azide, atrial natriuretic peptide) inhibited PI turnover. In low calcium buffer where serotonin mediated cGMP formation is inhibited, enhanced PI responses were observed that may be due to the removal of cGMP tone. Additionally, neither PI turnover or cGMP formation are inhibited by pertussis toxin treatment.; The structure-activity data may aid in the development of drugs which can be used to therapeutically target the 5-HT{dollar}sb{lcub}rm 1C{rcub}{dollar} receptor. Phosphoinositide turnover is generally calcium mobilizing while cyclic GMP elevation is associated with calcium buffering processes. The linkage and opposing role the two second messenger systems have in choroid plexus and elsewhere may be part of a mechanism which prevents toxicity associated with calcium signalling.