Inositol 1,4,5-trisphosphate receptors (IP3R) are intracellular Ca2+ channels localized to the endoplasmic reticulum (ER) membranes in almost every cell type. The rapid flux of Ca2+ through IP3R channels from the ER to the cytosol is central to numerous and markedly different cellular actions, ranging from contraction to secretion, from proliferation to cell death. Despite established significance of IP3Rs in physiology and pathology, the molecular mechanisms underlying function of these channels, both in native and disease states, remain poorly understood. The long-term goals of our research are to understand the mechanisms of ion permeation and gating in the family of IP3R channels, and how intracellular binding partners regulate the channel function. This proposal builds on extensive advances we made recently in structural studies of neuronal type 1 IP3R (IP3R1), the predominant type of IP3-gated Ca2+ release channel in cerebellar Purkinje cells.
We aim to uncover high-resolution architecture of the entire tetrameric IP3R1 and to delineate conformational changes in the channel that underlie its gating motion and regulation by an array of intracellular molecules ranging from ions and small chemical compounds to proteins. Our research efforts will include cryo- EM structure determination, biochemistry, biophysical, mutagenesis and electrophysiological studies to address channel structure-function. Built upon the complementary expertise of established investigators with compelling preliminary data support, the proposed studies will unveil the structural and mechanistic basis for IP3R function and will elucidate how defects in mechanisms regulating the channel?s gating can lead to abnormal cell Ca2+ levels underlying numerous diseases. Our research is innovative since little is known at the atomic level about the IP3R function. With these studies accomplished, we will establish a detailed structural framework for understanding how the IP3R selectively senses and decodes multiple ligand-binding signals into gating motions that enable the passage of Ca2+ through the channel. This knowledge is crucial for developing new ways to control channel function. Overall, the proposed studies are highly significant, as they will provide valuable mechanistic insights into Ca2+ transfer across biological membranes illuminating the pathological consequences of deregulated Ca2+ signaling, that will ultimately aid in search for novel therapies targeting the IP3R channel family.

Public Health Relevance

Inositol 1,4,5-trisphosphate receptors (IP3Rs) belong to a family of intracellular calcium channels that are ubiquitously expressed in all tissues and play central roles in maintenance and regulation of cell calcium homeostasis. Dysfunction of IP3Rs is linked to numerous human diseases, including stroke, neurodegenerative diseases and cancer. This proposal aims to understand the detailed structure and mechanisms of IP3R channel that will contribute to the development of new therapies for treatments of disorders related with abnormal cell calcium homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM072804-10A1
Application #
9995271
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nie, Zhongzhen
Project Start
2005-03-11
Project End
2024-02-29
Budget Start
2020-04-15
Budget End
2021-02-28
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
Fan, Guizhen; Baker, Mariah R; Wang, Zhao et al. (2018) Cryo-EM reveals ligand induced allostery underlying InsP3R channel gating. Cell Res 28:1158-1170
Baker, Mariah R; Fan, Guizhen; Serysheva, Irina I (2017) Structure of IP3R channel: high-resolution insights from cryo-EM. Curr Opin Struct Biol 46:38-47
Wang, Zhao; Fan, Guizhen; Hryc, Corey F et al. (2017) An allosteric transport mechanism for the AcrAB-TolC multidrug efflux pump. Elife 6:
Serysheva, Irina I; Baker, Mariah R; Fan, Guizhen (2017) Structural Insights into IP3R Function. Adv Exp Med Biol 981:121-147
Yi, Ping; Wang, Zhao; Feng, Qin et al. (2017) Structural and Functional Impacts of ER Coactivator Sequential Recruitment. Mol Cell 67:733-743.e4
Jarius, Sven; Ringelstein, Marius; Haas, Jürgen et al. (2016) Inositol 1,4,5-trisphosphate receptor type 1 autoantibodies in paraneoplastic and non-paraneoplastic peripheral neuropathy. J Neuroinflammation 13:278
Baker, Mariah R; Fan, Guizhen; Serysheva, Irina I (2015) Single-Particle Cryo-EM of the Ryanodine Receptor Channel in an Aqueous Environment. Eur J Transl Myol 25:4803
Baker, Mariah R; Fan, Guizhen; Serysheva, Irina I (2015) Single-particle cryo-EM of the ryanodine receptor channel in an aqueous environment. Eur J Transl Myol 25:35-48
Fan, Guizhen; Baker, Matthew L; Wang, Zhao et al. (2015) Gating machinery of InsP3R channels revealed by electron cryomicroscopy. Nature 527:336-41
Jarius, Sven; Scharf, Madeleine; Begemann, Nora et al. (2014) Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia. J Neuroinflammation 11:206

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