C-terminal amino acids in the type I transmembrane domain of L-type lectin VIP36 affect γ-secretase susceptibility

Hua, Zhihai; Watanabe, Ryoma; Fukunaga, Taku; Matsui, Yojiro; Matsuoka, Mayu; Yamaguchi, Shoya; Tanabe, Shun-ya; Yamamoto, Miyu; Tamura-Kawakami, Keiko; Takagi, Junichi; Kajita, Mihoko; Futai, Eugene; Shirakabe, Kyoko

doi:10.1016/j.bbrc.2024.149504

Biochemical and Biophysical Research Communications

2024

DOI: 10.1016/j.bbrc.2024.149504

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C-terminal amino acids in the type I transmembrane domain of L-type lectin VIP36 affect γ-secretase susceptibility

Zhihai Hua,

Ryoma Watanabe,

Taku Fukunaga

et al.

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2024

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Regulation of Kv1.2 redox-sensitive gating by the transmembrane lectin LMAN2

Lamothe,

Das,

Wong

et al. 2024

Preprint

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Kv1.2 potassium channels influence excitability and action potential propagation in the nervous system. Unlike closely-related Kv1 channels, Kv1.2 exhibits highly variable voltage-dependence of gating, attributed to regulation by unidentified extrinsic factors. Variable Kv1.2 gating is strongly influenced by the extracellular redox potential, and we demonstrate that Kv1.2 currents in dorsal root ganglion sensory neurons exhibit similar variability and redox sensitivity as observed when the channel is heterologously expressed in cell lines. We used a functional screening approach to test the effects of candidate regulatory proteins on Kv1.2 gating, using patch clamp electrophysiology. Among 52 candidate genes tested, we observed that co-expression with the transmembrane lectin LMAN2 led to a pronounced gating shift of Kv1.2 activation to depolarized voltages in CHO and L(tk-) cell lines, caused by deceleration of activation kinetics. Overexpression of LMAN2 promoted a slow gating mode of Kv1.2 that mimics the functional outcomes of extracellular reducing conditions, and enhanced sensitivity to extracellular reducing agents. In contrast, shRNA-mediated knockdown of endogenous LMAN2 in cell lines reduced Kv1.2 redox sensitivity and gating variability. Kv1.2 sensitivity to LMAN2 is abolished by mutation of neighboring residues F251 and T252 in the intracellular S2-S3 linker, and these also abolish redox-dependent modulation of Kv1.2, suggesting that LMAN2 is an important contributor to the mechanism of redox sensitivity. In conclusion, we identified LMAN2 as a candidate regulatory protein that influences redox-dependent modulation of Kv1.2, and clarified the structural elements of the channel that are required for sensitivity.

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Regulation of Kv1.2 redox-sensitive gating by the transmembrane lectin LMAN2

Lamothe,

Das,

Wong

et al. 2024

Preprint

View full text Add to dashboard Cite

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C-terminal amino acids in the type I transmembrane domain of L-type lectin VIP36 affect γ-secretase susceptibility

Cited by 1 publication

References 35 publications

Regulation of Kv1.2 redox-sensitive gating by the transmembrane lectin LMAN2

Regulation of Kv1.2 redox-sensitive gating by the transmembrane lectin LMAN2

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