Activity-dependent expression of inositol 1,4,5-trisphosphate receptor type 1 in hippocampal neurons

There are several lines of evidence showing that synaptic activity regulates the level of expression of inositol 1,4,5-trisphosphate receptor type 1 (IP(3)R1) in neurons. In this study, we examined the effect of chronic activity blockade on the localization and level of IP(3)R1 expression in cultured hippocampal neurons. We found that chronic blockade of NMDA receptors (NMDARs), one of the major Ca2+-permeable ion channels, increased the number of neurons that express a high level of IP(3)R1 without any apparent changes in its intracellular localization. Interestingly, this up-regulation was time-dependent; there was no clear change in IP(3)R1 expression level up to day 5 of the NMDAR blockade, but expression increased at day 6, and the increased expression level persisted for at least a week. The up-regulation of IP(3)R1 depended on transcription and protein synthesis and required cAMP-dependent protein kinase activity. Moreover, although most of the control neurons did not respond to the metabotropic glutamate receptor (mGluR) stimulation, the 2-amino-5-phosphonopentanoic acid-treated neurons with high IP(3)R1 expression became sensitive to mGluR stimulation. Furthermore, we also found that hippocampal neurons transiently overexpressing green fluorescent protein-tagged IP(3)R1 released Ca2+ in response to mGluR and muscarinic acetylcholine receptor stimulation. These findings suggested that chronic NMDAR blockade increased the IP(3)R1 expression and enhanced sensitivity to mGluR stimulation. The change in IP(3)R1 expression level in response to alteration of synaptic activity may be an important determinant of the sensitivity of Ca2+ stores to G-protein-coupled receptor stimulation and would help to maintain intracellular Ca2+ homeostasis in hippocampal neurons.