The antidepressant bupropion is a negative allosteric modulator of serotonin type 3A receptors.
The FDA-approved antidepressant and smoking cessation drug bupropion is known to inhibit dopamine and norepinephrine reuptake transporters, as well as nicotinic acetylcholine receptors (nAChRs) which are cation-conducting members of the Cys-loop superfamily of ion channels, and more broadly pentameric ligand-gated ion channels (pLGICs). In the present study, we examined the ability of bupropion and its primary metabolite hydroxybupropion to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs), and further characterized bupropion's pharmacological effects at these receptors. Mouse 5-HT3ARs were heterologously expressed in HEK-293 cells or Xenopus laevis oocytes for equilibrium binding studies. In addition, the latter expression system was utilized for functional studies by employing two-electrode voltage-clamp recordings. Both bupropion and hydroxybupropion inhibited serotonin-gated currents from 5-HT3ARs reversibly and dose-dependently with inhibitory potencies of 87 μM and 112 μM, respectively. Notably, the measured IC50value for hydroxybupropion is within its therapeutically-relevant concentrations. The blockade by bupropion was largely non-competitive and non-use-dependent. Unlike its modulation at cation-selective pLGICs, bupropion displayed no significant inhibition of the function of anion-selective pLGICs. In summary, our results demonstrate allosteric blockade by bupropion of the 5-HT3AR. Importantly, given the possibility that bupropion's major active metabolite may achieve clinically relevant concentrations in the brain, our novel findings delineate a not yet identified pharmacological principle underlying its antidepressant effect.
Department of Cell Physiology and Molecular Biophysics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Center for Membrane Protein Research, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. Electronic address: akash.pandhare@ttuhsc.edu.
Akash
A
Pandhare
Department of Cell Physiology and Molecular Biophysics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; The Clark Scholar Program, Texas Tech University, Lubbock, TX 79409, USA. Electronic address: apappu@standford.edu.
Aneesh Satya
AS
Pappu
Department of Neurology, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA. Electronic address: henrik.wilms@ttuhsc.edu.
Henrik
H
Wilms
Center for Membrane Protein Research, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA. Electronic address: michael.blanton@ttuhsc.edu.
Michael Paul
MP
Blanton
Department of Cell Physiology and Molecular Biophysics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Center for Membrane Protein Research, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. Electronic address: michaela.jansen@ttuhsc.edu.
Michaela
M
Jansen
D000494:Allosteric Regulation; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000493:pharmacokinetics*; D016642:Bupropion / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D017829:Granisetron / Q000493:pharmacokinetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D012701:Serotonin / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000493:pharmacokinetics*; D014982:Xenopus laevis
D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; D017829:Granisetron; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D058831:Serotonin 5-HT3 Receptor Antagonists; C511230:Htr3a protein, mouse; C580748:hydroxybupropion
5-HT(3A) receptors; Antidepressant; Bupropion; Hydroxybupropion; Pentameric ligand-gated ion channels
Science. 2013 Aug 30;341(6149):1016-20
23990563
Pharmacol Rev. 2007 Dec;59(4):360-417
18160701
J Physiol. 1991 Sep;441:121-36
1687746
Mol Psychiatry. 2003 Nov;8(12):994-1007
14647397
Eur J Neurosci. 2002 Feb;15(3):449-57
11876772
Eur J Clin Pharmacol. 1981;21(2):127-35
6804243
Drugs Exp Clin Res. 2001;27(3):113-8
11447769
J Pharmacol Exp Ther. 2003 Aug;306(2):595-604
12730353
J Pharmacol Exp Ther. 2009 May;329(2):838-47
19188483
J Affect Disord. 2006 May;92(1):79-90
16516303
Drugs. 1991 Oct;42(4):551-68
1723361
Sci Rep. 2016 Apr 01;6:23798
27033153
Mol Pharmacol. 2004 Sep;66(3):675-82
15322260
Cell Tissue Res. 2006 Nov;326(2):573-81
16826372
Mol Pharmacol. 2007 Oct;72 (4):1024-32
17628012
J Pharmacol Exp Ther. 1998 Jun;285(3):1219-25
9618425
Nature. 1987 Dec 24-31;330(6150):746-8
3696238
J Physiol. 2000 Dec 1;529 Pt 2:373-83
11101647
Biochemistry. 2009 Oct 6;48(39):9278-86
19715355
J Neurochem. 1993 Feb;60(2):730-7
8419547
Biol Psychiatry. 2006 Jun 15;59(12):1151-9
16566899
J Gen Physiol. 2008 Feb;131(2):137-46
18227272
Psychopharmacology (Berl). 1993;112(1 Suppl):S60-7
7831442
Eur J Pharmacol. 2007 Mar 29;560(1):1-8
17316606
J Clin Psychiatry. 2003 Sep;64(9):1025-30
14628977
Nature. 1999 Jan 28;397(6717):359-63
9950429
J Physiol. 1998 Jun 15;509 ( Pt 3):683-94
9596791
Mol Pharmacol. 2008 Nov;74(5):1407-16
18678621
Eur J Pharmacol. 2014 Oct 5;740:103-11
25016090
Neuron. 1988 Sep;1(7):615-21
3272181
Biochemistry. 2012 Mar 27;51(12):2425-35
22394379
J Clin Pharmacol. 1997 Aug;37(8):737-43
9378846
Eur Neuropsychopharmacol. 2000 Mar;10(2):77-95
10706989
J Physiol. 1994 Dec 1;481 ( Pt 2):311-23
7537814
Mol Pharmacol. 1994 Dec;46(6):1120-8
7808432
J Neurosci. 2004 Jan 28;24(4):895-906
14749434
Gastroenterology. 2005 May;128(5):1317-26
15887114
J Pharmacol Exp Ther. 1999 Jan;288(1):88-92
9862757
Mol Pharmacol. 2007 Jul;72(1):8-17
17392525
Mol Neurobiol. 2007 Apr;35(2):160-74
17917105
Curr Pharm Des. 2006;12(28):3615-30
17073663
J Biol Chem. 1999 Oct 22;274(43):30799-810
10521471
Schmerz. 2003 Jun;17(3):200-3
12789487
J Neurochem. 2007 Jan;100(2):395-405
17064350
Eur J Pharmacol. 2008 Feb 12;580(3):291-7
18082160
Gene. 2003 May 22;310:101-11
12801637
Nature. 2003 Jul 17;424(6946):321-4
12867984
Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1430-4
8434003
CNS Neurol Disord Drug Targets. 2007 Apr;6(2):127-40
17430150
Anesth Analg. 1991 Jun;72(6):751-5
1827966
Neuron. 1992 Jan;8(1):199-203
1346089
J Clin Psychiatry. 1983 May;44(5 Pt 2):79-81
6406469
Adv Biochem Psychopharmacol. 1982;31:277-86
6282058
J Gen Physiol. 1989 May;93(5):785-811
2472461
J Neurosci. 1994 Dec;14(12):7747-60
7996209
Nature. 1989 Jun 29;339(6227):706-9
2472553
Neurogastroenterol Motil. 2002 Dec;14(6):611-23
12464083
Neuropharmacology. 1993 Dec;32(12):1325-31
8152523
Mol Pharmacol. 1994 Mar;45(3):546-54
8145738
J Neurosci. 2010 Dec 15;30(50):16796-808
21159951
J Neurochem. 1989 Dec;53(6):1787-93
2809591
Neuron. 2014 Feb 19;81(4):873-87
24462040
Mol Pharmacol. 1999 Feb;55(2):269-78
9927618
J Clin Psychiatry. 1995 Sep;56(9):395-401
7665537
J Neurosci. 2002 Aug 1;22(15):6732-41
12151552
J Neurosci. 1997 May 1;17(9):3157-67
9096150
Biochem Pharmacol. 1989 May 15;38(10):1693-5
2543418
J Biol Chem. 1951 Nov;193(1):265-75
14907713
Neuroscience. 1989;31(2):393-400
2797443
Neurogastroenterol Motil. 2010 Feb;22(2):168-72, e52
19863635
N Engl J Med. 1997 Oct 23;337(17):1195-202
9337378
J Gen Physiol. 1990 Dec;96(6):1177-98
2286832
Prim Care Companion J Clin Psychiatry. 2004;6(4):159-166
15361919
J Biol Chem. 2012 Nov 23;287(48):40239-45
23038271
Scand J Rheumatol. 2004;33(4):267-70
15370724
Pharmacogenomics. 2008 May;9(5):501-4
18466097
Pharmacol Rev. 2009 Mar;61(1):98-114
19270242
Nature. 2011 Feb 24;470(7335):535-9
21350486
Br J Pharmacol. 2013 Jun;169(4):736-47
23489111
Biochem Pharmacol. 2003 Dec 1;66(11):2125-32
14609737
Br J Pharmacol. 1988 Apr;93(4):985-93
2898961
J Pharmacol Exp Ther. 2000 Oct;295(1):321-7
10991997
Science. 1991 Oct 18;254(5030):432-7
1718042
Life Sci. 2000;66(1):31-4
10658921
Thromb Haemost. 2008 Apr;99(4):784-6
18392340
Scand J Rheumatol Suppl. 2004;119:51-4
15515415
Scand J Rheumatol Suppl. 2004;119:9-11
15515405
Neuropharmacology. 2003 Dec;45(7):964-76
14573389
J Neurosci. 2002 Sep 1;22(17):7389-97
12196560
Eur J Pharmacol. 2003 Aug 1;474(1):85-93
12909199