Improved calcium sensor GCaMP-X overcomes the calcium channel perturbations induced by the calmodulin in GCaMP

Yaxiong Yang, Nan Liu, Yuanyuan He, Yuxia Liu, Lin Ge, Linzhi Zou, Sen Song, Wei Xiong and Xiaodong Liu ()
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Yaxiong Yang: Tsinghua University
Nan Liu: Tsinghua University
Yuanyuan He: Tsinghua University
Yuxia Liu: Tsinghua University
Lin Ge: Tsinghua University
Linzhi Zou: Tsinghua University
Sen Song: Tsinghua University
Wei Xiong: Tsinghua University
Xiaodong Liu: Tsinghua University

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: Abstract GCaMP, one popular type of genetically-encoded Ca2+ indicator, has been associated with various side-effects. Here we unveil the intrinsic problem prevailing over different versions and applications, showing that GCaMP containing CaM (calmodulin) interferes with both gating and signaling of L-type calcium channels (CaV1). GCaMP acts as an impaired apoCaM and Ca2+/CaM, both critical to CaV1, which disrupts Ca2+ dynamics and gene expression. We then design and implement GCaMP-X, by incorporating an extra apoCaM-binding motif, effectively protecting CaV1-dependent excitation–transcription coupling from perturbations. GCaMP-X resolves the problems of detrimental nuclear accumulation, acute and chronic Ca2+ dysregulation, and aberrant transcription signaling and cell morphogenesis, while still demonstrating excellent Ca2+-sensing characteristics partly inherited from GCaMP. In summary, CaM/CaV1 gating and signaling mechanisms are elucidated for GCaMP side-effects, while allowing the development of GCaMP-X to appropriately monitor cytosolic, submembrane or nuclear Ca2+, which is also expected to guide the future design of CaM-based molecular tools.

Date: 2018
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DOI: 10.1038/s41467-018-03719-6

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