Effects of Calretinin on Ca2+ Signals in Cerebellar Granule Cells: Implications of Cooperative Ca2+ Binding

• Published in: Cerebellum (London, England) England), 2012-03, Vol.11 (1), p.102-120
• Main Author: Saftenku, Elena È.
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Animals; Binding Sites - physiology; Biomedical and Life Sciences; Biomedicine; Calbindin 2; Calcium Signaling - physiology; Calcium-Binding Proteins - metabolism; Calcium-Binding Proteins - physiology; Cerebellar Cortex - cytology; Cerebellar Cortex - physiology; Cytoplasmic Granules - metabolism; Cytoplasmic Granules - physiology; Models, Neurological; Neurobiology; Neurology; Neurons - cytology; Neurons - metabolism; Neurons - physiology; Neurosciences; Original Paper; Potassium Channels, Calcium-Activated - metabolism; Potassium Channels, Calcium-Activated - physiology; Rats; S100 Calcium Binding Protein G - metabolism; S100 Calcium Binding Protein G - physiology
• ISSN: 1473-4222; 1473-4230
• DOI: 10.1007/s12311-011-0263-4

Calretinin is thought to be the main endogenous calcium buffer in cerebellar granule cells (GrCs). However, little is known about the impact of cooperative Ca 2+ binding to calretinin on highly localized and more global (regional) Ca 2+ signals in these cells. Using numerical simulations, we show that an essential property of calretinin is a delayed equilibration with Ca 2+ . Therefore, the amount of Ca 2+ , which calretinin can accumulate with respect to equilibrium levels, depends on stimulus conditions. Based on our simulations of buffered Ca 2+ diffusion near a single Ca 2+ channel or a large cluster of Ca 2+ channels and previous experimental findings that 150 μM 1,2-bis(o-aminophenoxy) ethane- N , N , N ′, N ′-tetraacetic acid (BAPTA) and endogenous calretinin have similar effects on GrC excitability, we estimated the concentration of mobile calretinin in GrCs in the range of 0.7–1.2 mM. Our results suggest that this estimate can provide a starting point for further analysis. We find that calretinin prominently reduces the action potential associated increase in cytosolic free Ca 2+ concentration ([Ca 2+ ] i ) even at a distance of 30 nm from a single Ca 2+ channel. In spite of a buildup of residual Ca 2+ , it maintains almost constant maximal [Ca 2+ ] i levels during repetitive channel openings with a frequency less than 80 Hz. This occurs because of accelerated Ca 2+ binding as calretinin binds more Ca 2+ . Unlike the buffering of high Ca 2+ levels within Ca 2+ nano/microdomains sensed by large conductance Ca 2+ -activated K + channels, the buffering of regional Ca 2+ signals by calretinin can never be mimicked by certain concentration of BAPTA under all different experimental conditions.