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result sql = Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states.
Tricyclic antidepressants inhibit homomeric Cys-loop receptors by acting at different conformational states.
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char = (;code = 40
char = 3;code = 51
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char = ;code = 32
char = (;code = 40
char = I;code = 73
char = C;code = 67
char = (;code = 40
char = 5;code = 53
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char = r;code = 114
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char = a;code = 97
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char = a;code = 97
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char = ,;code = 44
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char = s;code = 115
char = s;code = 115
char = a;code = 97
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char = s;code = 115
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char = o;code = 111
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char = a;code = 97
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char = n;code = 110
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char = a;code = 97
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char = ;code = 32
char = t;code = 116
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char = e;code = 101
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char = u;code = 117
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char = s;code = 115
char = h;code = 104
char = a;code = 97
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char = e;code = 101
char = d;code = 100
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char = a;code = 97
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char = e;code = 101
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char = l;code = 108
char = u;code = 117
char = l;code = 108
char = a;code = 97
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char = d;code = 100
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char = a;code = 97
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char = o;code = 111
char = m;code = 109
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char = w;code = 119
char = h;code = 104
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char = e;code = 101
char = y;code = 121
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char = i;code = 105
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char = h;code = 104
char = i;code = 105
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char = t;code = 116
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char = e;code = 101
char = l;code = 108
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char = p;code = 112
char = e;code = 101
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char = n;code = 110
char = g;code = 103
char = .;code = 46
char = ;code = 32
char = S;code = 83
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char = l;code = 108
char = e;code = 101
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char = a;code = 97
char = l;code = 108
char = p;code = 112
char = h;code = 104
char = a;code = 97
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char = -;code = 45
char = 5;code = 53
char = H;code = 72
char = T;code = 84
char = (;code = 40
char = 3;code = 51
char = A;code = 65
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char = ;code = 32
char = c;code = 99
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char = a;code = 97
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char = n;code = 110
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char = i;code = 105
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char = c;code = 99
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char = a;code = 97
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char = t;code = 116
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char = w;code = 119
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char = I;code = 73
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char = a;code = 97
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result sql = 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.

Publication: Eur. J. Pharmacol. 2008 Apr 14 ;584(1)::30-9. :doi: 10.1016/j.ejphar.2008.01.023.
Publication Date: 2008 Apr 14
Study Author(s): Gumilar, Fernanda;Bouzat, Cecilia;
Institution: Instituto de Investigaciones Bioquímicas, Universidad Nacional del Sur-CONICET, Camino La Carrindanga Km 7, B8000FWB, Bahía Blanca, Argentina.
Shortcut link to this study:
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.
PMID: 18314100

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