Positive and negative modulation of nicotinic receptors

Desformylflustrabromine (dFBr) and [3H]dFBr-Labeled Binding Sites in a Nicotinic Acetylcholine Receptor

“…Positive allosteric modulators (PAMs) of nAChRs have been introduced as a novel physiologic approach to enhance nAChR function (Faghih et al, 2008;Arias, 2010;Williams et al, 2011). A nAChR PAM, by definition, binds at site(s) distinct from the ACh binding (i.e., orthosteric) site and enhances the effects of ACh.…”

Interaction of nicotinic receptors with bupropion: Structural, functional, and pre-clinical perspectives

“…On the other hand, Zn inhibition is mediated by a site located on the 2(+)/4(-) subunit interface from both (4)3(2)2 and (4)2(2)3 stoichio-metries [i.e., LS and high sensitivity (HS) to agonist activation, respectively]. Additional site-directed mutagenesis and molecular modeling studies on rat 42 and 44 AChRs suggest that the potentiating effect of Zn 2+ is mediated by binding to the 4(-)/2(+) subunit interface (more specifically by coordination with 4-His162 and 4-Glu59) [92,93,94] . These results contrast with our findings indicating that the BP binding site is mainly located in the middle of the AChR ion channel (see next section and Figure 3).…”

“…Moreover, Zn 2+ increases the inhibitory activity of antidepressants on AChRs [86] , which seems to be related to the observed enhanced efficacy of several antidepressants in the presence of this cation in animal models of depression [85,87,88] . Interestingly, Zn 2+ potentiates different non-α7 AChRs [85,[89][90][91][92][93][94] . The results on α4β4 AChRs indicate that the pre-application of BP greatly decreases the potentiating action elicited by Zn 2+ and that the presence of this cation increases the inhibitory strength of BP [88] .…”

Functional and Structural Interaction of (−)-Reboxetine with the Human α4β2 Nicotinic Acetylcholine Receptor

“…Nevertheless, SNRIs also behave as noncompetitive antagonists (NCAs) of several nicotinic acetylcholine receptors (nAChRs) (Hennings et al, 1999;Izaguirre et al, 1997;Miller et al, 2002;Rana et al, 1993;reviewed in Arias et al, 2006). nAChRs are members of the Cys-loop ligand-gated ion channel superfamily, which also includes types A and C g-aminobutyric acid, type 3 serotonin, and glycine receptors (reviewed in Arias et al, 2006;Arias, 2010;Albuquerque et al, 2009). The antidepressant-induced inhibition of one or more nAChR subtypes might be related to their therapeutic actions.…”