LINGO1 is a regulatory subunit of large conductance, Ca2+-activated potassium channels

Srikanth Dudem; Roddy J Large; Shruti Kulkarni; Heather McClafferty; Irina G Tikhonova; Gerard P Sergeant; Keith D Thornbury; Michael J Shipston; Brian A Perrino; Mark A Hollywood

doi:10.1073/pnas.1916715117

LINGO1 is a regulatory subunit of large conductance, Ca2+-activated potassium channels

Srikanth Dudem, Roddy J Large, Shruti Kulkarni, Heather McClafferty, Irina G Tikhonova, Gerard P Sergeant, Keith D Thornbury, Michael J Shipston, Brian A Perrino, Mark A Hollywood

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Abstract

LINGO1 is a transmembrane protein that is up-regulated in the cerebellum of patients with Parkinson's disease (PD) and Essential Tremor (ET). Patients with additional copies of the LINGO1 gene also present with tremor. Pharmacological or genetic ablation of large conductance Ca2+-activated K+ (BK) channels also result in tremor and motor disorders. We hypothesized that LINGO1 is a regulatory BK channel subunit. We show that 1) LINGO1 coimmunoprecipitated with BK channels in human brain, 2) coexpression of LINGO1 and BK channels resulted in rapidly inactivating BK currents, and 3) LINGO1 reduced the membrane surface expression of BK channels. These results suggest that LINGO1 is a regulator of BK channels, which causes a "functional knockdown" of these currents and may contribute to the tremor associated with increased LINGO1 levels.

Original language	English
Pages (from-to)	2194
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	4
Early online date	13 Jan 2020
DOIs	https://doi.org/10.1073/pnas.1916715117
Publication status	Early online date - 13 Jan 2020
Externally published	Yes

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10.1073/pnas.1916715117Licence: CC BY-NC-ND

LLINGO1 is a regulatory subunit of large conductance, Ca2+-activated potassium channels
Copyright 2020 the authors. This is an open access article published under a Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Final published version, 1.15 MBLicence: CC BY-NC-ND

Irina Tikhonova
- i.tikhonovaqub.acuk
- School of Pharmacy - Reader
- Material and Advanced Technologies for Healthcare
Person: Academic

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Dudem, S., Large, R. J., Kulkarni, S., McClafferty, H., Tikhonova, I. G., Sergeant, G. P., Thornbury, K. D., Shipston, M. J., Perrino, B. A., & Hollywood, M. A. (2020). LINGO1 is a regulatory subunit of large conductance, Ca2+-activated potassium channels. Proceedings of the National Academy of Sciences of the United States of America, 117(4), 2194. https://doi.org/10.1073/pnas.1916715117

Dudem, Srikanth ; Large, Roddy J ; Kulkarni, Shruti ; McClafferty, Heather ; Tikhonova, Irina G ; Sergeant, Gerard P ; Thornbury, Keith D ; Shipston, Michael J ; Perrino, Brian A ; Hollywood, Mark A. / LINGO1 is a regulatory subunit of large conductance, Ca2+-activated potassium channels. In: Proceedings of the National Academy of Sciences of the United States of America. 2020 ; Vol. 117, No. 4. pp. 2194.

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title = "LINGO1 is a regulatory subunit of large conductance, Ca2+-activated potassium channels",

abstract = "LINGO1 is a transmembrane protein that is up-regulated in the cerebellum of patients with Parkinson's disease (PD) and Essential Tremor (ET). Patients with additional copies of the LINGO1 gene also present with tremor. Pharmacological or genetic ablation of large conductance Ca2+-activated K+ (BK) channels also result in tremor and motor disorders. We hypothesized that LINGO1 is a regulatory BK channel subunit. We show that 1) LINGO1 coimmunoprecipitated with BK channels in human brain, 2) coexpression of LINGO1 and BK channels resulted in rapidly inactivating BK currents, and 3) LINGO1 reduced the membrane surface expression of BK channels. These results suggest that LINGO1 is a regulator of BK channels, which causes a {"}functional knockdown{"} of these currents and may contribute to the tremor associated with increased LINGO1 levels.",

author = "Srikanth Dudem and Large, {Roddy J} and Shruti Kulkarni and Heather McClafferty and Tikhonova, {Irina G} and Sergeant, {Gerard P} and Thornbury, {Keith D} and Shipston, {Michael J} and Perrino, {Brian A} and Hollywood, {Mark A}",

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Dudem, S, Large, RJ, Kulkarni, S, McClafferty, H, Tikhonova, IG, Sergeant, GP, Thornbury, KD, Shipston, MJ, Perrino, BA & Hollywood, MA 2020, 'LINGO1 is a regulatory subunit of large conductance, Ca2+-activated potassium channels', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 4, pp. 2194. https://doi.org/10.1073/pnas.1916715117

LINGO1 is a regulatory subunit of large conductance, Ca2+-activated potassium channels. / Dudem, Srikanth; Large, Roddy J; Kulkarni, Shruti; McClafferty, Heather; Tikhonova, Irina G; Sergeant, Gerard P; Thornbury, Keith D; Shipston, Michael J; Perrino, Brian A; Hollywood, Mark A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, No. 4, 13.01.2020, p. 2194.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - LINGO1 is a regulatory subunit of large conductance, Ca2+-activated potassium channels

AU - Dudem, Srikanth

AU - Large, Roddy J

AU - Kulkarni, Shruti

AU - McClafferty, Heather

AU - Tikhonova, Irina G

AU - Sergeant, Gerard P

AU - Thornbury, Keith D

AU - Shipston, Michael J

AU - Perrino, Brian A

AU - Hollywood, Mark A

PY - 2020/1/13

Y1 - 2020/1/13

N2 - LINGO1 is a transmembrane protein that is up-regulated in the cerebellum of patients with Parkinson's disease (PD) and Essential Tremor (ET). Patients with additional copies of the LINGO1 gene also present with tremor. Pharmacological or genetic ablation of large conductance Ca2+-activated K+ (BK) channels also result in tremor and motor disorders. We hypothesized that LINGO1 is a regulatory BK channel subunit. We show that 1) LINGO1 coimmunoprecipitated with BK channels in human brain, 2) coexpression of LINGO1 and BK channels resulted in rapidly inactivating BK currents, and 3) LINGO1 reduced the membrane surface expression of BK channels. These results suggest that LINGO1 is a regulator of BK channels, which causes a "functional knockdown" of these currents and may contribute to the tremor associated with increased LINGO1 levels.

AB - LINGO1 is a transmembrane protein that is up-regulated in the cerebellum of patients with Parkinson's disease (PD) and Essential Tremor (ET). Patients with additional copies of the LINGO1 gene also present with tremor. Pharmacological or genetic ablation of large conductance Ca2+-activated K+ (BK) channels also result in tremor and motor disorders. We hypothesized that LINGO1 is a regulatory BK channel subunit. We show that 1) LINGO1 coimmunoprecipitated with BK channels in human brain, 2) coexpression of LINGO1 and BK channels resulted in rapidly inactivating BK currents, and 3) LINGO1 reduced the membrane surface expression of BK channels. These results suggest that LINGO1 is a regulator of BK channels, which causes a "functional knockdown" of these currents and may contribute to the tremor associated with increased LINGO1 levels.

U2 - 10.1073/pnas.1916715117

DO - 10.1073/pnas.1916715117

M3 - Article

C2 - 31932443

VL - 117

SP - 2194

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 0027-8424

IS - 4

ER -

LINGO1 is a regulatory subunit of large conductance, Ca2+-activated potassium channels

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