Inositol 1,4,5-Trisphosphate Receptor Type 3 Regulates Neuronal Growth Cone Sensitivity to Guidance Signals

Abstract

During neurodevelopment, the growth cone deciphers directional information from extracellular guidance cues presented as shallow concentration gradients via signal amplification. However, it remains unclear how the growth cone controls this amplification process during its navigation through an environment in which basal cue concentrations vary widely. Here, we identified inositol 1,4,5-trisphosphate (IP 3 ) receptor type 3 as a regulator of axonal sensitivity to guidance cues in vitro and in vivo. Growth cones lacking the type 3 subunit are hypersensitive to nerve growth factor (NGF), an IP 3 -dependent attractive cue, and incapable of turning toward normal concentration ranges of NGF to which wild-type growth cones respond. This is due to globally, but not asymmetrically, activated Ca 2+ signaling in the hypersensitive growth cones. Remarkably, lower NGF concentrations can polarize growth cones for turning if IP 3 receptor type 3 is deficient. These data suggest a subtype-specific IP 3 receptor function in sensitivity adjustment during axon navigation.

Chaperone Sigma1R and Antidepressant Effect

“…It is possible that the effect of ketamine on Sigma1R does not mediate a rapid antidepressant effect but contributes to the duration of the drug’s effect through the induction of neuroplasticity processes. For example, the role of IP 3 R3 in NGF-stimulated neuronal growth was revealed [ 199 ]. Sigma1R might be involved in this process by interacting with IP 3 R3 in the MAM region and stabilizing its conformation [ 59 ].…”

Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

“…ITPRs are differently expressed in human tissues, as reported in Table 1, obtained with data retrieved from the Human Protein Atlas [20]. The effects of ITPRs have been extensively studied in preclinical models [21][22][23][24][25][26][27][28][29]. Here, we offer an overview of the human pathologies where ITPR alterations have a clear causative role.…”