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Front Neurosci. 2015 Jan 21;8:453. doi: 10.3389/fnins.2014.00453. eCollection 2014.

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.

Author information

  • 1Department of Medicine, Mayo Clinic Rochester, MN, USA.
  • 2Richard D. Berlin Center for Cell Analysis and Modeling, University of Connecticut Health Center Farmington, CT, USA.

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.

KEYWORDS:

Purkinje; carbonic anhydrase related proteins; computational; homer; inositol 1,4,5-trisphosphate receptor 1; model; spinocerebellar ataxia; translational

PMID:
25653583
PMCID:
PMC4300941
DOI:
10.3389/fnins.2014.00453
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