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 (IP₃R1) in neurons. In this study, we examined the effect of chronic activity blockade on the localization and level of IP₃R1 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 ₃R1 without any apparent changes in its intracellular localization. Interestingly, this up-regulation was time-dependent; there was no clear change in IP₃R1 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 IP₃R1 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 IP₃R1 expression became sensitive to mGluR stimulation. Furthermore, we also found that hippocampal neurons transiently overexpressing green fluorescent protein-tagged IP₃R1 released Ca²⁺ in response to mGluR and muscarinic acetylcholine receptor stimulation. These findings suggested that chronic NMDAR blockade increased the IP₃R1 expression and enhanced sensitivity to mGluR stimulation. The change in IP₃R1 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.