Calcineurin controls inositol 1,4,5-trisphosphate type 1 receptor expression in neurons

Abstract

In the central nervous system, release of Ca 2+from intracellular stores contributes to numerous functions, including neurotransmitter release and long-term potentiation and depression. We have investigated the developmental profile and the regulation of inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) in primary cultures of cerebellar granule cells. The expression of both receptor types increases during development. Whereas the expression of type 1 IP3R appears to be regulated by Ca 2+influx through L type channels or N-methyl-d-aspartate (NMDA) receptors, RyR levels increase independently of Ca 2+. The main target of Ca 2+-influx-regulating IP3R expression is the Ca 2+calmodulin-dependent protein phosphatase calcineurin, because pharmacological blockade of this protein abolishes IP3R expression. Although calcineurin has been shown to regulate the phosphorylation state of the IP3R, the effect described here is at the transcriptional level because IP3R mRNA changes in parallel with protein levels. Thus, calcineurin plays a dual role in IP3R-mediated Ca 2+signaling: it regulates IP3R function by dephosphorylation in the short-term time scale and IP3R expression over more extended periods.