Interaction of bupropion and zinc with neuronal nicotinic acetylcholine receptors

Garcı́a-Colunga, Jesús; Godoy-García, Ulises; Vázquez-Gómez, Elizabeth

doi:10.1016/j.neuropharm.2011.07.009

Cited by 10 publications

(9 citation statements)

References 55 publications

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“…Similar results are shown with other antidepressants at 5-HT 3 R (Eisensamer, 2003) and with bupropion at nAChR (e.g. α 3 β 2 , α 4 β 2 , α 3 β 4 ) with predictions for an external binding site for bupropion (Garcia-Colunga, 2011; Slemmer, 2000). Considering different binding sites within the family of AChR (Pandhare, 2012), bupropion may have distinct binding sites in each channel (Arias, 2009b).…”

Section: Discussionsupporting

confidence: 76%

“…Pre-incubation with inhibitor lead to an increased inhibition in all cases when compared to co-application, indicating that the block is non-use dependent for both receptors. Our observation that bupropion’s inhibition of 5-HT 3 R is voltage-independent additionally concurs with it not acting as an open channel blocker (Choi, 2003; Garcia-Colunga, 2011; Gumilar, 2003; Gumilar, 2008; Slemmer, 2000). Similar results are shown with other antidepressants at 5-HT 3 R (Eisensamer, 2003) and with bupropion at nAChR (e.g.…”

Section: Discussionsupporting

confidence: 74%

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Bupropion inhibits serotonin type 3AB heteromeric channels at a physiologically relevant concentration

Stuebler

Jansen

2019

Preprint

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Bupropion, a FDA-approved antidepressant and smoking cessation aid, blocks dopamine and norepinephrine reuptake transporters and non-competitively inhibits nicotinic acetylcholine (nACh) and serotonin type 3A (5-HT 3 ) receptors. 5-HT 3 receptors are pentameric ligand-gated ion channels that regulate synaptic activity in the central and peripheral nervous system pre-and postsynaptically. In the present study, we examined and compared the effect of bupropion and its active metabolite hydroxybupropion on homomeric 5-HT 3A and heteromeric mouse 5-HT 3AB receptors expressed in Xenopus laevis oocytes using two-electrode voltage clamp experiments. Co-application of bupropion or hydroxybupropion with 5-HT dose-dependently inhibited 5-HT-induced currents in 5-HT 3AB Rs (IC 50 = 866 μ M and 505 μ M, respectively) but potentiated 5-HT-induced currents at low (30-50 μ M) concentrations. The corresponding IC 50 s for bupropion and hydroxybupropion with 5-HT 3A R were 10-and 5-fold lower, respectively (87 μ M and 113 μ M), and no potentiation was observed. The inhibition of 5-HT 3A R and 5-HT 3AB R was non-use dependent and voltage-independent, indicating bupropion is not an open channel blocker. The inhibition by bupropion was reversible and time-dependent. Of note, pre-incubation with a low concentration of bupropion that mimics therapeutic drug conditions significantly inhibited 5-HT induced currents in 5-HT 3A and even more so 5-HT 3AB receptors. In summary, our results indicate that bupropion inhibits 5-HT 3AB R, as well as homomeric receptors, and that this inhibition takes place at clinically-relevant concentrations. Inhibition of 5-HT 3 receptors by bupropion may contribute to its desired and/or undesired clinical effects. Significance Statement5-HT 3AB receptors are found in brain areas involved in mood regulation. Clinical studies indicate that antagonizing these receptors was successful in treating mood and anxiety disorders. Some currently clinically available antidepressants and antipsychotics act as antagonists of 5-HT 3 receptors. Previously, bupropion was shown to be an antagonist at homopentameric 5-HT 3A receptors. The present work provides novel insights into the pharmacological effects bupropion exerts on heteromeric 5-HT 3AB receptors. The results advance the knowledge on the clinical effect of bupropion as an antidepressant. the functional responses observed in native tissues (Davies, 1999; Dubin, 1999; Hussy, 1994; Maricq, 1991). When compared to 5-HT 3A R, 5-HT 3AB R differs in agonist concentration-response curves, shows increased single-channel conductance and desensitization, and an altered current-voltage relationship (Davies, 1999; Dubin, 1999; Kelley, 2003b; Thompson, 2013).The 5-HT 3 R is widely distributed in the central and peripheral nervous systems, and on extraneuronal cells, such as monocytes, chondrocytes, T-cells, and synovial tissue (Fiebich, 2004). In the periphery, 5-HT 3 Rs are found in the autonomic, sensory and enteric nervous systems (Faerber, 2007) where they are involved in...

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Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 74%

Bupropion inhibits serotonin type 3AB heteromeric channels at a physiologically relevant concentration

Stuebler

Jansen

2019

Preprint

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“…(e.g., a 3 b 2 , a 4 b 2 , a 3 b 4 ) with predictions for an external binding site for bupropion (Slemmer et al, 2000;García-Colunga et al, 2011). Considering different binding sites within the family of AChRs (Pandhare et al, 2012), bupropion may have distinct binding sites in each channel (Arias et al, 2009).…”

Section: Discussionmentioning

confidence: 95%

Bupropion Inhibits Serotonin Type 3AB Heteromeric Channels at Clinically Relevant Concentrations

Stuebler

Jansen

2019

Mol Pharmacol

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Bupropion, a Food and Drug Administration-approved antidepressant and smoking cessation aid, blocks dopamine and norepinephrine reuptake transporters and noncompetitively inhibits nicotinic acetylcholine and serotonin (5-HT) type 3A receptors (5-HT 3A Rs). 5-HT 3 receptors are pentameric ligandgated ion channels that regulate synaptic activity in the central and peripheral nervous system, presynaptically and postsynaptically. In the present study, we examined and compared the effect of bupropion and its active metabolite hydroxybupropion on mouse homomeric 5-HT 3A and heteromeric 5-HT 3AB receptors expressed in Xenopus laevis oocytes using two-electrode voltage clamp experiments. Coapplication of bupropion or hydroxybupropion with 5-HT dose dependently inhibited 5-HT-induced currents in heteromeric 5-HT type 3AB receptors (5-HT 3AB Rs) (IC 50 5 840 and 526 mM, respectively). The corresponding IC 50 s for bupropion and hydroxybupropion for homomeric 5-HT 3A Rs were 10-and 5-fold lower, respectively (87 and 113 mM). The inhibition of 5-HT 3A Rs and 5-HT 3AB Rs was non-use dependent and voltage independent, suggesting bupropion is not an open channel blocker. The inhibition by bupropion was reversible and time-dependent. Of note, preincubation with a low concentration of bupropion that mimics therapeutic drug conditions inhibits 5-HT-induced currents in 5-HT 3A and 5-HT 3AB receptors considerably. In summary, we demonstrate that bupropion inhibits heteromeric 5-HT 3AB Rs as well as homomeric 5-HT 3A Rs. This inhibition occurs at clinically relevant concentrations and may contribute to bupropion's clinical effects. SIGNIFICANCE STATEMENT Clinical studies indicate that antagonizing serotonin (5-HT) type 3AB (5-HT 3AB) receptors in brain areas involved in mood regulation is successful in treating mood and anxiety disorders. Previously, bupropion was shown to be an antagonist at homopentameric 5-HT type 3A receptors. The present work provides novel insights into the pharmacological effects that bupropion exerts on heteromeric 5-HT 3AB receptors, in particular when constantly present at low, clinically attainable concentrations. The results advance the knowledge on the clinical effects of bupropion as an antidepressant.

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“…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] .…”

Section: Pharmacological Activity Of Bp and Its Metabolites And Derivmentioning

confidence: 99%

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

Arias¹,

Biała²,

Kruk-Słomka³

et al. 2014

Receptor Clin Invest

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Besides the antidepressant activity of bupropion (BP), preclinical studies in rodents provide evidence that this compound and its hydroxyl metabolites can attenuate nicotine withdrawal, reversing both the physical and negative affective aspects of nicotine abstinence. Co-interactions of BP with nicotine or other psychostimulants influence decrease anxiety-and cognitive-related processes. BP also attenuates the reinstatement of nicotine-induced conditioned place preference in rats caused by a priming dose of nicotine, morphine, cannabinoids, or ethanol.

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Interaction of bupropion and zinc with neuronal nicotinic acetylcholine receptors

Cited by 10 publications

References 55 publications

Bupropion inhibits serotonin type 3AB heteromeric channels at a physiologically relevant concentration

Bupropion inhibits serotonin type 3AB heteromeric channels at a physiologically relevant concentration

Bupropion Inhibits Serotonin Type 3AB Heteromeric Channels at Clinically Relevant Concentrations

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

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