Linker flexibility of IVS3-S4 loops modulates voltage-dependent activation of L-type Ca2+ channels

• Published in: Channels (Austin, Tex.) Vol. 11; no. 1; pp. 34 - 45
• Main Authors: Liu, Nan, Liu, Yuxia, Yang, Yaxiong, Liu, Xiaodong
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 02.01.2017
• Subjects: channels; L-type Ca; linker flexibility; Research Paper; S3-S4 loop; voltage sensing domain; voltage-dependent activation
• ISSN: 1933-6950; 1933-6969
• DOI: 10.1080/19336950.2016.1207023

Extracellular S3-S4 linkers of domain IV (IVS3-S4) of L-type Ca 2+ channels (Ca V 1) are subject to alternative splicing, resulting into distinct gating profiles serving for diverse physiological roles. However, it has remained elusive what would be the determining factor of IVS3-S4 effects on Ca V 1 channels. In this study, we systematically compared IVS3-S4 variants from Ca V 1.1-1.4, and discover that the flexibility of the linker plays a prominent role in gating characteristics. Chimeric analysis and mutagenesis demonstrated that changes in half activation voltage (V 1/2 ) or activation time constant (τ) are positively correlated with the numbers of flexible glycine residues within the linker. Moreover, antibodies that reduce IVS3-S4 flexibility negatively shifted V 1/2 , emerging as a new category of Ca V 1 enhancers. In summary, our results suggest that the flexibility or rigidity of IVS3-S4 linker underlies its modulations on Ca V 1 activation (V 1/2 and τ), paving the way to dissect the core mechanisms and to develop innovative perturbations pertaining to voltage-sensing S4 and its vicinities.