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Article

Rescue of Misfolded Organic Cation Transporter 3 Variants

by
Thomas J. F. Angenoorth
1,†,
Julian Maier
1,†,
Stevan Stankovic
1,
Shreyas Bhat
1,2,3,
Sonja Sucic
1,
Michael Freissmuth
1,
Harald H. Sitte
1,* and
Jae-Won Yang
1,*
1
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Währingerstraße 13A, 1090 Vienna, Austria
2
Department of Physics, Université de Montréal, 1375 Avenue Thérèse-Lavoie-Roux, Montréal, QC H3T 1J4, Canada
3
Department of Pharmacology and Physiology, Université de Montréal, 2960 Chemin de la Tour, Montréal, QC H3T 1J4, Canada
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2023, 12(1), 39; https://doi.org/10.3390/cells12010039
Submission received: 18 November 2022 / Revised: 13 December 2022 / Accepted: 19 December 2022 / Published: 22 December 2022
(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)
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Abstract

Organic cation transporters (OCTs) are membrane proteins that take up monoamines, cationic drugs and xenobiotics. We previously reported novel missense mutations of organic cation transporter 3 (OCT3, SLC22A3), some with drastically impacted transport capabilities compared to wildtype. For some variants, this was due to ER retention and subsequent degradation of the misfolded transporter. For other transporter families, it was previously shown that treatment of misfolded variants with pharmacological and chemical chaperones could restore transport function to a certain degree. To investigate two potentially ER-bound, misfolded variants (D340G and R348W), we employed confocal and biochemical analyses. In addition, radiotracer uptake assays were conducted to assess whether pre-treatment with chaperones could restore transporter function. We show that pre-treatment of cells with the chemical chaperone 4-PBA (4-phenyl butyric acid) leads to increased membrane expression of misfolded variants and is associated with increased transport capacity of D340G (8-fold) and R348W (1.5 times) compared to untreated variants. We herein present proof of principle that folding-deficient SLC22 transporter variants, in particular those of OCT3, are amenable to rescue by chaperones. These findings need to be extended to other SLC22 members with corroborated disease associations.
Keywords: 4-PBA; µ-pifithrin; 17-DMAG; progesterone; corticosterone; pharmacochaperoning; chemical chaperone 4-PBA; µ-pifithrin; 17-DMAG; progesterone; corticosterone; pharmacochaperoning; chemical chaperone

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MDPI and ACS Style

Angenoorth, T.J.F.; Maier, J.; Stankovic, S.; Bhat, S.; Sucic, S.; Freissmuth, M.; Sitte, H.H.; Yang, J.-W. Rescue of Misfolded Organic Cation Transporter 3 Variants. Cells 2023, 12, 39. https://doi.org/10.3390/cells12010039

AMA Style

Angenoorth TJF, Maier J, Stankovic S, Bhat S, Sucic S, Freissmuth M, Sitte HH, Yang J-W. Rescue of Misfolded Organic Cation Transporter 3 Variants. Cells. 2023; 12(1):39. https://doi.org/10.3390/cells12010039

Chicago/Turabian Style

Angenoorth, Thomas J. F., Julian Maier, Stevan Stankovic, Shreyas Bhat, Sonja Sucic, Michael Freissmuth, Harald H. Sitte, and Jae-Won Yang. 2023. "Rescue of Misfolded Organic Cation Transporter 3 Variants" Cells 12, no. 1: 39. https://doi.org/10.3390/cells12010039

APA Style

Angenoorth, T. J. F., Maier, J., Stankovic, S., Bhat, S., Sucic, S., Freissmuth, M., Sitte, H. H., & Yang, J.-W. (2023). Rescue of Misfolded Organic Cation Transporter 3 Variants. Cells, 12(1), 39. https://doi.org/10.3390/cells12010039

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