Interaction of bupropion with muscle-type nicotinic acetylcholine receptors in different conformational states

Hugo R. Arias, Fernanda Gumilar, Avraham Rosenberg, Katarzyna M. Targowska-Duda, Dominik Feuerbach, Krzysztof Jozwiak, Ruin Moaddel, Irving W. Wainer, Cecilia Bouzat

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

To characterize the binding sites and the mechanisms of inhibition of bupropion on muscle-type nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The results established that bupropion (a) inhibits epibatidine-induced Ca2+ influx in embryonic muscle AChRs, (b) inhibits adult muscle AChR macroscopic currents in the resting/activatable state with ∼100-fold higher potency compared to that in the open state, (c) increases the desensitization rate of adult muscle AChRs from the open state and impairs channel opening from the resting state, (d) inhibits binding of [ 3H]TCP and [3H]imipramine to the desensitized/ carbamylcholine-bound Torpedo AChR with higher affinity compared to the resting/α-bungarotoxin-bound AChR, (e) binds to the Torpedo AChR in either state mainly by an entropy-driven process, and (f) interacts with a binding domain located between the serine (position 6′) and valine (position 13′) rings, by a network of van der Waals, hydrogen bond, and polar interactions. Collectively, our data indicate that bupropion first binds to the resting AChR, decreasing the probability of ion channel opening. The remnant fraction of open ion channels is subsequently decreased by accelerating the desensitization process. Bupropion interacts with a luminal binding domain shared with PCP that is located between the serine and valine rings, and this interaction is mediated mainly by an entropy-driven process.

Original languageEnglish
Pages (from-to)4506-4518
Number of pages13
JournalBiochemistry
Volume48
Issue number21
DOIs
StatePublished - 2 Jun 2009
Externally publishedYes

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Bupropion
Nicotinic Receptors
Cholinergic Receptors
Muscle
Muscles
Torpedo
epibatidine
Valine
Entropy
Ion Channels
Serine
Bungarotoxins
Imipramine
Carbachol
Hydrogen
Hydrogen bonds
Binding Sites

Cite this

Arias, H. R., Gumilar, F., Rosenberg, A., Targowska-Duda, K. M., Feuerbach, D., Jozwiak, K., ... Bouzat, C. (2009). Interaction of bupropion with muscle-type nicotinic acetylcholine receptors in different conformational states. Biochemistry, 48(21), 4506-4518. https://doi.org/10.1021/bi802206k
Arias, Hugo R. ; Gumilar, Fernanda ; Rosenberg, Avraham ; Targowska-Duda, Katarzyna M. ; Feuerbach, Dominik ; Jozwiak, Krzysztof ; Moaddel, Ruin ; Wainer, Irving W. ; Bouzat, Cecilia. / Interaction of bupropion with muscle-type nicotinic acetylcholine receptors in different conformational states. In: Biochemistry. 2009 ; Vol. 48, No. 21. pp. 4506-4518.
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abstract = "To characterize the binding sites and the mechanisms of inhibition of bupropion on muscle-type nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The results established that bupropion (a) inhibits epibatidine-induced Ca2+ influx in embryonic muscle AChRs, (b) inhibits adult muscle AChR macroscopic currents in the resting/activatable state with ∼100-fold higher potency compared to that in the open state, (c) increases the desensitization rate of adult muscle AChRs from the open state and impairs channel opening from the resting state, (d) inhibits binding of [ 3H]TCP and [3H]imipramine to the desensitized/ carbamylcholine-bound Torpedo AChR with higher affinity compared to the resting/α-bungarotoxin-bound AChR, (e) binds to the Torpedo AChR in either state mainly by an entropy-driven process, and (f) interacts with a binding domain located between the serine (position 6′) and valine (position 13′) rings, by a network of van der Waals, hydrogen bond, and polar interactions. Collectively, our data indicate that bupropion first binds to the resting AChR, decreasing the probability of ion channel opening. The remnant fraction of open ion channels is subsequently decreased by accelerating the desensitization process. Bupropion interacts with a luminal binding domain shared with PCP that is located between the serine and valine rings, and this interaction is mediated mainly by an entropy-driven process.",
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Arias, HR, Gumilar, F, Rosenberg, A, Targowska-Duda, KM, Feuerbach, D, Jozwiak, K, Moaddel, R, Wainer, IW & Bouzat, C 2009, 'Interaction of bupropion with muscle-type nicotinic acetylcholine receptors in different conformational states', Biochemistry, vol. 48, no. 21, pp. 4506-4518. https://doi.org/10.1021/bi802206k

Interaction of bupropion with muscle-type nicotinic acetylcholine receptors in different conformational states. / Arias, Hugo R.; Gumilar, Fernanda; Rosenberg, Avraham; Targowska-Duda, Katarzyna M.; Feuerbach, Dominik; Jozwiak, Krzysztof; Moaddel, Ruin; Wainer, Irving W.; Bouzat, Cecilia.

In: Biochemistry, Vol. 48, No. 21, 02.06.2009, p. 4506-4518.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Interaction of bupropion with muscle-type nicotinic acetylcholine receptors in different conformational states

AU - Arias, Hugo R.

AU - Gumilar, Fernanda

AU - Rosenberg, Avraham

AU - Targowska-Duda, Katarzyna M.

AU - Feuerbach, Dominik

AU - Jozwiak, Krzysztof

AU - Moaddel, Ruin

AU - Wainer, Irving W.

AU - Bouzat, Cecilia

PY - 2009/6/2

Y1 - 2009/6/2

N2 - To characterize the binding sites and the mechanisms of inhibition of bupropion on muscle-type nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The results established that bupropion (a) inhibits epibatidine-induced Ca2+ influx in embryonic muscle AChRs, (b) inhibits adult muscle AChR macroscopic currents in the resting/activatable state with ∼100-fold higher potency compared to that in the open state, (c) increases the desensitization rate of adult muscle AChRs from the open state and impairs channel opening from the resting state, (d) inhibits binding of [ 3H]TCP and [3H]imipramine to the desensitized/ carbamylcholine-bound Torpedo AChR with higher affinity compared to the resting/α-bungarotoxin-bound AChR, (e) binds to the Torpedo AChR in either state mainly by an entropy-driven process, and (f) interacts with a binding domain located between the serine (position 6′) and valine (position 13′) rings, by a network of van der Waals, hydrogen bond, and polar interactions. Collectively, our data indicate that bupropion first binds to the resting AChR, decreasing the probability of ion channel opening. The remnant fraction of open ion channels is subsequently decreased by accelerating the desensitization process. Bupropion interacts with a luminal binding domain shared with PCP that is located between the serine and valine rings, and this interaction is mediated mainly by an entropy-driven process.

AB - To characterize the binding sites and the mechanisms of inhibition of bupropion on muscle-type nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The results established that bupropion (a) inhibits epibatidine-induced Ca2+ influx in embryonic muscle AChRs, (b) inhibits adult muscle AChR macroscopic currents in the resting/activatable state with ∼100-fold higher potency compared to that in the open state, (c) increases the desensitization rate of adult muscle AChRs from the open state and impairs channel opening from the resting state, (d) inhibits binding of [ 3H]TCP and [3H]imipramine to the desensitized/ carbamylcholine-bound Torpedo AChR with higher affinity compared to the resting/α-bungarotoxin-bound AChR, (e) binds to the Torpedo AChR in either state mainly by an entropy-driven process, and (f) interacts with a binding domain located between the serine (position 6′) and valine (position 13′) rings, by a network of van der Waals, hydrogen bond, and polar interactions. Collectively, our data indicate that bupropion first binds to the resting AChR, decreasing the probability of ion channel opening. The remnant fraction of open ion channels is subsequently decreased by accelerating the desensitization process. Bupropion interacts with a luminal binding domain shared with PCP that is located between the serine and valine rings, and this interaction is mediated mainly by an entropy-driven process.

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