The Type I Inositol 1,4,5-Trisphosphate Receptor Interacts with Protein 4.1N to Mediate Neurite Formation through Intracellular Ca2+ Waves

[摘要] Ca²⁺ waves are an important mechanism for encoding Ca²⁺ signaling information, but the molecular basis for wave formation and how this regulates neuronal function is not entirely understood. Using nerve growth factor-differentiated PC12 cells as a model system, we investigated the interaction between the type I inositol 1,4,5-trisphosphate receptor (IP3R1) and the cytoskeletal linker, protein 4.1N, to examine the relationship between Ca²⁺ wave formation and neurite development. This was examined using RNAi and overexpressed dominant negative binding regions of each protein. Confocal microscopy was used to monitor neurite formation and Ca²⁺ waves. Knockdown of IP3R1 or 4.1N attenuated neurite formation, as did binding regions of IP3R1 and 4.1N, which colocalized with endogenous 4.1N and IP3R1, respectively. Upon stimulation with the IP3-producing agonist carbachol, both RNAi and dominant negative molecules shifted signaling events from waves to homogeneous patterns of Ca²⁺ release. These findings provide evidence that IP3R1 localization, via protein 4.1N, is necessary for Ca²⁺ wave formation, which in turn mediates neurite formation.

[学科分类] 神经科学

[关键词] Type I inositol 1;4;5-trisphosphate receptor;Protein 4.1N;Ca2+ waves;Neuron