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The structural requirements for phorbol esters to enhance serotonin and acetylcholine release from rat brain cortex
Author(s) -
Iannazzo L,
Kotsonis P,
Majewski H
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702627
Subject(s) - phorbol , serotonin , protein kinase c , acetylcholine , chemistry , neurotransmitter , pharmacology , biochemistry , medicine , endocrinology , biology , kinase , receptor
The effects of various phorbol‐based protein kinase C (PKC) activators on the electrical stimulation‐induced (S‐I) release of serotonin and acetylcholine was studied in rat brain cortical slices pre‐incubated with [ 3 H]‐serotonin or [ 3 H]‐choline to investigate possible structure‐activity relationships. 4β‐Phorbol 12,13‐dibutyrate (4βPDB, 0.1–3.0 μ M ), enhanced S‐I release of serotonin in a concentration‐dependent manner whereas the structurally related inactive isomer 4α‐phorbol 12, 13‐dibutyrate (4αPDB) and phorbol 13‐acetate (PA) were without effect. Another group of phorbol esters containing a common 13‐ester substituent (phorbol 12,13‐diacetate, PDA; phorbol 12‐myristate 13‐acetate, PMA; phorbol 12‐methylaminobenzoate 13‐acetate, PMBA) also enhanced S‐I serotonin release with PMA being least potent. The deoxyphorbol monoesters, 12‐deoxyphorbol 13‐acetate (dPA), 12‐deoxyphorbol 13‐angelate (dPAng), 12‐deoxyphorbol 13‐phenylacetate (dPPhen) and 12‐deoxyphorbol 13‐isobutyrate (dPiB) enhanced S‐I serotonin release but 12‐deoxyphorbol 13‐tetradecanoate (dPT) was without effect. The 20‐acetate derivatives of dPPhen and dPAng were less effective in enhancing S‐I serotonin release compared to the parent compounds. With acetylcholine release all phorbol esters tested had a far lesser effect when compared to their facilitatory action on serotonin release with only 4βPDB, PDA, dPA, dPAng and dPiB having significant effects. The effects of the phorbol esters on serotonin release were not correlated with their reported in vitro affinity and isozyme selectivity for PKC. A comparison across three transmitter systems (noradrenaline, dopamine, serotonin) suggests basic similarities in the structural requirements of phorbol esters to enhance transmitter release with short chain substituted mono‐ and diesters of phorbol being more potent facilitators of release than the long chain esters. Some compounds notably PDA, PMBA, dPPhen, dPPhenA had different potencies across noradrenaline, dopamine and serotonin.British Journal of Pharmacology (1999) 127 , 1177–1189; doi: 10.1038/sj.bjp.0702627