Attenuation of Cyclic AMP Production by Carbamazepine

Abstract

The anticonvulsant carbamazepine is an effective treatment both for epilepsy and for bipolar affective disorder, but the molecular mechanism(s) underlying its therapeutic effects have not been identified. We have found that carbamazepine exerts significant inhibitory effects on the cyclic AMP (cAMP) generating system. Within the clinical therapeutic range (-~5Oj.tM), carbamazepine inhibited both basal and forskolin-stimulated cAMP production, without having any significant effects on phosphodiesterase activity. Carbamazepine also exerted its inhibitory effects on the cAMP generating system in pertussis toxin-treated cells, suggesting that the action of carbamazepine was likely mediated through an inhibitory guanine nucleotide binding protein-independent mechanism. A forskolin affinity purification column was used to purify adenylyl cyclases from rat cerebral cortex, and we found that. carbamazepine inhibited both basal and forskolin-stimulated activity of purified adenylyl cyclase. We also investigated the effects of carbamazepine on the levels of the transcription factor, cAMP response element binding protein in the phosphorylated (active) state, and found that carbamazepine significantly inhibited forskolin-induced phosphorylation of the cAMP response element binding protein. The data indicate that carbamazepine inhibits adenylyl cyclase activity as well as the downstream effects of activation of adenylyl cyclase. Key Words: Carbamazepine-Adenylyl cyclase-Seizure-Mania-Anticonvulsant--Cyclic AMP response element binding protein.

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

“…The GHSR is also known to stimulate adenylyl cyclase [5]. Stimulation of adenylyl cyclase has been implicated in pro-convulsant effects [53][54][55][56][57]. Thus, one can theorize that GHSR desensitization/inverse agonism should result in anticonvulsant effects through inactivation of the CREB pathway, diminished IP 3 -dependent Ca 2+ release, and decreased adenylyl cyclase activity.…”

Mood stabilizer psychopharmacology

“…As discussed in an earlier section, evidence suggests that carbamazepine may have direct inhibitory effects on adenylate cyclase [61], and in a number of studies has been shown to attenuate stimulated cyclic AMP signaling [54,[56][57][58][59]. This finding is especially interesting noting that lithium also attenuates stimulated cyclic AMP signaling [13].…”

“…Surprisingly, in spite of the mRNA changes, it has not been consistently found that lithium changes the total protein levels of G protein subunits. This evidence eventually led to studies suggesting that carbamazepine may directly inhibit adenylate cyclase [61]. Thus, Chen et al reported that at therapeutic concentrations carbamazepine inhibited both basal and stimulated cyclic AMP production [61].…”

“…This evidence eventually led to studies suggesting that carbamazepine may directly inhibit adenylate cyclase [61]. Thus, Chen et al reported that at therapeutic concentrations carbamazepine inhibited both basal and stimulated cyclic AMP production [61]. Carbamazepine exerted this effect regardless of whether adenylate cyclase coupled receptors, or adenylate cyclase itself was stimulated, thus suggesting the possibility of a direct inhibitory effect.…”

“…Carbamazepine exerted this effect regardless of whether adenylate cyclase coupled receptors, or adenylate cyclase itself was stimulated, thus suggesting the possibility of a direct inhibitory effect. Furthermore, these effects where found in adenylate cyclase extracts; suggesting that carbamazepine inhibits adenylase cyclase directly, or acts via a closely associated factor that purifies with the enzyme [61]. Most of the evidence discussed has been accumulated during acute treatment, and it remains to be seen if this action can be temporally associated with carbamazepine's therapeutic effects in treating mania.…”