Integration of modeling with experimental and clinical findings synthesizes and refines the central role of inositol 1,4,5-trisphosphate receptor 1 in spinocerebellar ataxia.

Sherry-Ann Brown,Leslie M Loew

doi:10.3389/fnins.2014.00453

Sherry-Ann Brown, Leslie M Loew

Open Access

https://doi.org/10.3389/fnins.2014.00453

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Abstract

A suite of models was developed to study the role of inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in spinocerebellar ataxias (SCAs). Several SCAs are linked to reduced abundance of IP3R1 or to supranormal sensitivity of the receptor to activation by its ligand inositol 1,4,5-trisphosphate (IP3). Detailed multidimensional models have been created to simulate biochemical calcium signaling and membrane electrophysiology in cerebellar Purkinje neurons. In these models, IP3R1-mediated calcium release is allowed to interact with ion channel response on the cell membrane. Experimental findings in mice and clinical observations in humans provide data input for the models. The SCA modeling suite helps interpret experimental results and provides suggestions to guide experiments. The models predict IP3R1 supersensitivity in SCA1 and compensatory mechanisms in SCA1, SCA2, and SCA3. Simulations explain the impact of calcium buffer proteins. Results show that IP3R1-mediated calcium release activates voltage-gated calcium-activated potassium channels in the plasma membrane. The SCA modeling suite unifies observations from experiments in a number of SCAs. The cadre of simulations demonstrates the central role of IP3R1.

Highlights

Several classes of spinocerebellar ataxia in humans and mice are associated with reduced IP3R1 levels (Matsumoto et al, 1996; Street et al, 1997; Zecevic et al, 1999; Lin et al, 2000; Ogura et al, 2001; Serra et al, 2004; Kurnellas et al, 2007; van de Leemput et al, 2007; Chou et al, 2008; Novak et al, 2010b; Castrioto et al, 2011; Marelli et al, 2011; Huang et al, 2012; Obayashi et al, 2012; Hansen et al, 2013; Sugawara et al, 2013) or increased sensitivity of the receptor to IP3 (Inoue et al, 2001; Chen et al, 2008; Liu et al, 2009), or both
Schorge et al argue that the unifying feature of many cerebellar ataxias is their impact on IP3R1 (Schorge et al, 2010)
The spinocerebellar ataxias (SCAs) suite examines the role of IP3R1 in SCA pathophysiology (Brown and Loew, 2012), with potential for translational studies

Summary

Introduction

Several classes of spinocerebellar ataxia in humans and mice are associated with reduced IP3R1 levels (Matsumoto et al, 1996; Street et al, 1997; Zecevic et al, 1999; Lin et al, 2000; Ogura et al, 2001; Serra et al, 2004; Kurnellas et al, 2007; van de Leemput et al, 2007; Chou et al, 2008; Novak et al, 2010b; Castrioto et al, 2011; Marelli et al, 2011; Huang et al, 2012; Obayashi et al, 2012; Hansen et al, 2013; Sugawara et al, 2013) or increased sensitivity of the receptor to IP3 (Inoue et al, 2001; Chen et al, 2008; Liu et al, 2009), or both.

Results

Conclusion