Copine-6 is a Ca2+ sensor for activity-induced AMPA receptor exocytosis
Jing Zhi Anson Tan,
Se Eun Jang,
Ana Batallas-Borja,
Nishita Bhembre,
Mintu Chandra,
Lingrui Zhang,
Huimin Guo,
Mitchell T. Ringuet,
Jocelyn Widagdo,
Brett M. Collins,
Victor Anggono
Affiliations
Jing Zhi Anson Tan
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; Corresponding author
Se Eun Jang
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Ana Batallas-Borja
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Nishita Bhembre
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Mintu Chandra
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
Lingrui Zhang
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Huimin Guo
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Mitchell T. Ringuet
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Jocelyn Widagdo
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
Brett M. Collins
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
Victor Anggono
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; Corresponding author
Summary: The recruitment of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors underlies the strengthening of neuronal connectivity during learning and memory. This process is triggered by N-methyl-D-aspartate (NMDA) receptor-dependent postsynaptic Ca2+ influx. Synaptotagmin (Syt)-1 and -7 have been proposed as Ca2+ sensors for AMPA receptor exocytosis but are functionally redundant. Here, we identify a cytosolic C2 domain-containing Ca2+-binding protein, Copine-6, that forms a complex with AMPA receptors. Loss of Copine-6 expression impairs activity-induced exocytosis of AMPA receptors in primary neurons, which is rescued by wild-type Copine-6 but not Ca2+-binding mutants. In contrast, Copine-6 loss of function does not affect steady-state expression or tetrodotoxin-induced synaptic upscaling of surface AMPA receptors. Loss of Syt-1/Syt-7 significantly reduces Copine-6 protein expression. Interestingly, overexpression of wild-type Copine-6, but not the Ca2+-binding mutants, restores activity-dependent exocytosis of AMPA receptors in Syt-1/Syt-7 double-knockdown neurons. We conclude that Copine-6 is a postsynaptic Ca2+ sensor that mediates AMPA receptor exocytosis during synaptic potentiation.
