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.