G protein β subunits regulate Cav3.3 T-type channel activity and current 
kinetics via interaction with the Casubv3.3 C-terminus

Jeong, Sua; Lee, Bo-Young; Rhee, Jeong Seop; Lee, Jung-Ha

doi:10.1016/j.bbamem.2024.184337

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G protein β subunits regulate Ca_v3.3 T-type channel activity and current kinetics via interaction with the Casub_v3.3 C-terminus

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Rhee, Jeong Seop
Research Group of Neurophysiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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引用

Jeong, S., Lee, B.-Y., Rhee, J. S., & Lee, J.-H. (2024). G protein β subunits regulate Ca_v3.3 T-type channel activity and current kinetics via interaction with the Casub_v3.3 C-terminus. Biochimica et Biophysica Acta: BBA, 1866(6):. doi:10.1016/j.bbamem.2024.184337.

引用: https://hdl.handle.net/21.11116/0000-000F-5676-C

要旨

Ca2+ influx through Cav3.3 T-type channel plays crucial roles in neuronal excitability and is subject to regulation by various signaling molecules. However, our understanding of the partners of Cav3.3 and the related regulatory pathways remains largely limited. To address this quest, we employed the rat Cav3.3 C-terminus as bait in yeast-two-hybrid screenings of a cDNA library, identifying rat Gβ2 as an interaction partner. Subsequent assays revealed that the interaction of Gβ2 subunit was specific to the Cav3.3 C-terminus. Through systematic dissection of the C-terminus, we pinpointed a 22 amino acid sequence (amino acids 1789–1810) as the Gβ2 interaction site. Coexpression studies of rat Cav3.3 with various Gβγ compositions were conducted in HEK-293 cells. Patch clamp recordings revealed that coexpression of Gβ2γ2 reduced Cav3.3 current density and accelerated inactivation kinetics. Interestingly, the effects were not unique to Gβ2γ2, but were mimicked by Gβ2 alone as well as other Gβγ dimers, with similar potencies. Deletion of the Gβ2 interaction site abolished the effects of Gβ2γ2. Importantly, these Gβ2 effects were reproduced in human Cav3.3. Overall, our findings provide evidence that Gβ(γ) complexes inhibit Cav3.3 channel activity and accelerate the inactivation kinetics through the Gβ interaction with the Cav3.3 C-terminus.