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Cryo-EM reveals the molecular mechanism of IP3 receptor channel opening

Photo of (L-R) Emily Schmitz wearing a blue top, Hirohide Takahashi, and Erkan Karakas wearing eye-glasses.
L-R: Emily Schmitz, Hirohide Takahashi, Erkan Karakas

By Emily Overway

Research led by co-first authors Emily Schmitz, a graduate student in the Chemical and Physical Biology program, and Hirohide Takahashi, a research instructor in molecular physiology and biophysics, identified the structure of the human type-3 inositol 1,4,5-triphosphate, or IP3, receptor in several conformations using cryo-electron microscopy. Schmitz and Takahasi, who work in the lab of Erkan Karakas, professor of molecular physiology and biophysics, published their research in March in Nature Communications.

We sat down with Karakas to learn more about the work.

What issue/problem does your research address?

IP3 receptors receive a diverse array of signals from hormones, growth factors, and neurotransmitters. They also detect changes in metabolic states. IP3 receptors respond to these signals and modulate downstream activity in all cell types by opening channel gates and allowing calcium to travel from the endoplasmic reticulum lumen to the cytoplasm; IP3 and Ca2+ are necessary for IP3 receptor activation, which is further potentiated by ATP binding.

There are three types of IP3 receptors (types 1-3) that are involved in distinct signaling pathways that regulate learning, fertilization, gene expression, and apoptosis. Disruption of IP3 receptor signaling is associated with several diseases, including cancer, diabetes, and neurological disorders. Recent structural studies revealed IP3 receptor architecture, but fundamental questions regarding the mechanisms of ligand interactions and channel gating remain mostly unanswered.

What was unique about your approach to the research?

We used extensive screening and data analysis to obtain the structure of the receptor in active conformation, which is a challenging task for IP3 receptors due to technical difficulties. In this study, we reported cryo-EM structures of the human type-3 IP3 receptor in multiple gating conformations: IP3-ATP-bound pre-active state with closed channels, IP3-ATP-Ca2+-bound active state with an open channel, and IP3-ATP-Ca2+-bound inactive state with a closed channel.

What were your findings?

IP3 receptors are ion channels that open pores through the membrane upon binding of chemical ligands. In this study, we determined the structure of the receptor in multiple functional positions, including one where the channel is open. The structures reveal, at atomic resolution, how IP3-induced conformational changes prime the receptor for activation by Ca2+, how Ca2+ binding leads to channel opening, and how ATP modulates the activity, providing insights into longstanding questions regarding the molecular mechanism underpinning receptor activation and gating.

What do you hope will be achieved with the research results in the short and long terms?

This study is fundamental for understanding IP3 receptor biology. It will serve as a foundation for future experiments addressing biophysical and functional questions related to IP3 receptors. It may also guide the design of pharmacological tools for targeting this class of proteins.

What are the benefits of this research?

Pathological dysregulation of IP3 receptors and calcium signaling is implicated in autoimmune, cancer, metabolic, and neurodegenerative diseases, making IP3 receptors promising targets for treatment of these diseases.

Where is this research taking you next? What will you personally be doing, or how will other researchers build on this work?

IP3 receptors are protein complexes involved in many physiological processes. Our lab will continue to expand our knowledge of these receptors using structural biology as the primary tool.


This work was funded by the National Institutes of Health, Vanderbilt University, the Vanderbilt Diabetes and Research Training Center, and the Molecular Biophysics Training Program.

The authors would like to extend special thanks to Dr. Kunpeng Li at Case Western Reserve University; Theo Humphreys at the Pacific Northwest Center for Cryo-EM; and Elad Binshtein, Melissa Chambers, and Scott Collier at Vanderbilt University, all of whom assisted in the work.