Abstract：
:Tricyclic antidepressants not only inhibit monoamine reuptake but also modulate Cys-loop receptors. However, it is not understood how this modulation is involved in their therapeutic effects. We analyzed the mechanisms of inhibition of homomeric 5-HT(3A) and alpha7-5HT(3A) receptors by tricyclic antidepressants at the single-channel and macroscopic current levels. These drugs reduce agonist-evoked currents in a noncompetitive and concentration-dependent manner. When they act on the open state, the reduction is similar for both receptors and it is voltage-dependent, thus suggesting an open-channel block process in which the blocked channel can either close or remain stabilized. By acting on the resting state, tricyclic antidepressants reduce the peak current in a voltage-independent manner, with a potency 6-fold higher for 5-HT(3A) than for alpha7-5HT(3A) (IC(50): 6 microM and 1 microM for alpha7-5HT(3A) and 5-HT(3A), respectively). Thus, tricyclic antidepressants may act on closed channels at the unshared extracellular domain from where they inhibit channel opening. Single alpha7-5HT(3A) channels in the continued presence of tricyclic antidepressants show: i) reduced open durations, compatible with open-channel block; ii) reduced burst durations, compatible with closing of blocked channels; and iii) reduced frequency of opening events, compatible with both impaired opening and stabilization of a closed state. In summary, our study reveals that tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting through different mechanisms at open and closed conformational states and probably at two different domains, namely, the pore in the open state and the extracellular domain in the closed state.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Gumilar F,Bouzat Cdoi
10.1016/j.ejphar.2008.01.023subject
Has Abstractpub_date
2008-04-14 00:00:00pages
30-9issue
1eissn
0014-2999issn
1879-0712pii
S0014-2999(08)00092-7journal_volume
584pub_type
杂志文章abstract：:Pharmacological experiments have implicated a role for serotonin (5-HT)(1A) receptors in the modulation of anxiety. More recent is the interest in corticotropin-releasing hormone (CRH) system as a potential target for the treatment of anxiety disorders. However, selective pharmacological tools for the CRH system are l...
journal_title：European journal of pharmacology
pub_type： 杂志文章,评审
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abstract：:Cordycepin, (3'-deoxyadenosine), a bioactive compound of Cordyceps militaris, has been shown to exhibit many pharmacological actions, such as anti-inflammatory, antioxidative and anticancer activities. Little is known about the neuroprotective action of cordycepin as well as its molecular mechanisms. In this study, co...
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journal_title：European journal of pharmacology
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doi：10.1016/0014-2999(89)90296-3
更新日期：1989-03-21 00:00:00
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journal_title：European journal of pharmacology
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journal_title：European journal of pharmacology
pub_type： 杂志文章
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pub_type： 杂志文章
doi：10.1016/j.ejphar.2011.10.017
更新日期：2011-12-30 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
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journal_title：European journal of pharmacology
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(80)90509-9
更新日期：1980-10-17 00:00:00
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journal_title：European journal of pharmacology
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doi：10.1016/j.ejphar.2006.10.047
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journal_title：European journal of pharmacology
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abstract：:There is evidence that bovine adrenal chromaffin cells are provided with both dihydropyridine-sensitive and -resistant voltage-sensitive Ca2+ influx pathways. Although recent electrophysiological work indicates that the dihydropyridine-resistant pathway is partially mediated by omega-conotoxin-sensitive and -insensiti...
journal_title：European journal of pharmacology
pub_type： 杂志文章
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更新日期：1993-02-15 00:00:00
