Abstract:
:A 3D model was developed and used to explore dynamics of phosphatidylinositol-4,5-bisphosphate (PIP2) signaling in cerebellar Purkinje neurons. Long-term depression in Purkinje neurons depends on coincidence detection of climbing fiber stimulus evoking extracellular calcium flux into the cell and parallel fiber stimulus evoking inositol-1,4,5-trisphosphate (IP3)-meditated calcium release from the endoplasmic reticulum. Experimental evidence shows that large concentrations of IP3 are required for calcium release. This study uses computational analysis to explore how the Purkinje cell provides sufficient PIP2 to produce large amounts of IP3. Results indicate that baseline PIP2 concentration levels in the plasma membrane are inadequate, even if the model allows for PIP2 replenishment by lateral diffusion from neighboring dendrite membrane. Lateral diffusion analysis indicates apparent anomalous diffusion of PIP2 in the spiny dendrite membrane, due to restricted diffusion through spine necks. Stimulated PIP2 synthesis and elevated spine PIP2 mediated by a local sequestering protein were explored as candidate mechanisms to supply sufficient PIP2. Stimulated synthesis can indeed lead to high IP3 amplitude of long duration; local sequestration produces high IP3 amplitude, but of short duration. Simulation results indicate that local sequestration could explain the experimentally observed finely tuned timing between parallel fiber and climbing fiber activation.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Brown SA,Morgan F,Watras J,Loew LMdoi
10.1529/biophysj.108.130195subject
Has Abstractpub_date
2008-08-01 00:00:00pages
1795-812issue
4eissn
0006-3495issn
1542-0086pii
biophysj.108.130195journal_volume
95pub_type
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