Forskolin and Phorbol Myristate Acetate Inhibit Intracellular Ca2+ Mobilization Induced by Amitriptyline and Bradykinin in Rat Frontocortical Neurons

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Abstract
Regulations of the increase in intracellular Ca2+ concentration ([Ca2+]i) and inositol 1,4,5-trisphosphate (IP3) production by increasing intracellular cyclic AMP (cAMP) levels or activating protein kinase C (PKC) were studied in rat frontocortical cultured neurons. Amitriptyline (AMI; 1 mM), a tricyclic antidepressant, and bradykinin (BK; 1 microM) stimulated IP3 production and caused transient [Ca2+]i increases. Pretreatment with forskolin (100 microM, 15 min) decreased the AMI- and BK-induced [Ca2+]i increases by 33 and 48%, respectively. However, this treatment had no effect on the AMI- and BK-induced IP3 productions. Dibutyryl-cAMP (2 mM, 15 min) also decreased the AMI- and BK-induced [Ca2+]i increases by 23 and 47%, respectively. H-8 (30 microM), an inhibitor of protein kinase A (PKA), attenuated the ability of forskolin to inhibit the AMI- and BK-induced [Ca2+]i increases, suggesting that the activation of cAMP/PKA was involved in these inhibitory effects of forskolin. On the other hand, forskolin treatment had no effect on 20 mM caffeine-, 10 microM glutamate-, or 50 mM K(+)-induced [Ca2+]i increases. Pretreatment with phorbol 12-myristate 13-acetate (PMA; 100 nM, 90 min) decreased both the AMI-induced [Ca2+]i increases and the IP3 production by 31 and 25%, respectively. H-7 (200 microM), an inhibitor of PKC, inhibited the ability of PMA to attenuate the [Ca2+]i increases. PMA also inhibited the BK-induced IP3 production and the [Ca2+]i increases.(ABSTRACT TRUNCATED AT 250 WORDS)

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