A high-performance genetically encoded sensor for cellular imaging of PKC activity in vivo

Takaki Yahiro, Landon Bayless-Edwards, James A. Jones, Yizhou Zhuo, Lei Ma, Maozhen Qin, Tianyi Mao () and Haining Zhong ()
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Takaki Yahiro: Oregon Health and Science University
Landon Bayless-Edwards: Oregon Health and Science University
James A. Jones: Oregon Health and Science University
Yizhou Zhuo: Oregon Health and Science University
Lei Ma: Oregon Health and Science University
Maozhen Qin: Oregon Health and Science University
Tianyi Mao: Oregon Health and Science University
Haining Zhong: Oregon Health and Science University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Neuromodulators impose powerful control over brain function via their regulation of intracellular signaling through G-protein coupled receptors. In contrast to those of Gs and Gi pathways, in vivo imaging of the signaling events downstream of Gq-coupled receptors remains challenging. Here, we introduce CKAR3, a genetically encoded fluorescence lifetime sensor that reports the activity of protein kinase C (PKC), a major downstream effector of the Gq pathway. CKAR3 exhibits a lifetime dynamic range 5-fold larger than any existing PKC sensor. It specifically detects PKC phosphorylation with seconds kinetics without perturbing neuronal functions. In vivo two-photon lifetime imaging of CKAR3 reveals tonic PKC activity in cortical neurons. Animal locomotion elicits robust PKC activity in sparse neuronal ensembles in the motor cortex. Both basal and locomotion-elicited PKC activities are in part mediated by muscarinic acetylcholine receptors. Overall, CKAR3 enables interrogation of Gq signaling dynamics mediated by PKC in behaving animals.

Date: 2025
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DOI: 10.1038/s41467-025-61729-7

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