Neural function : metabolism and actions of inositol metabolites in mammalian brain

Abstract

In the nervous system, a variety of cell types respond to external stimuli through the inositol lipid signalling pathways. The stimulus-coupled sequence of intracellular events has been investigated in a homogeneous model system, the cloned mammalian neural cell line NG115-401L. The neural peptide bradykinin stimulates a rapid production of identified inositol phosphate isomers and an intracellular Ca ²⁺ discharge followed by a persistent plasma membrane influx. The temporal sequence suggests that Ins(1,4,5) P ₃ or Ins(1,3,4,5) P ₄ or both may coordinate these events in a neuronal cell, as has been suggested in other cell types. Thapsigargin, an irritant and tumour-promoting plant product, produces calcium transients in the absence of inositol phosphate production, and may provide a new tool for investigating the interactions between inositol phosphates and changes in cellular calcium homeostasis. In the 401L line, high levels of radiolabelled Ins P ₅ and Ins P ₆ have been detected, which has led to the evaluation of their possible occurrence and actions in normal brain. Both Ins P ₅ and Ins P ₆ are produced from a radiolabelled myo-inositol precursor in intact mature brain in a region-specific manner. This suggests that both inositol polyphosphates may be end products of regionally regulated biosynthetic pathways. When microinjected into a nucleus of the brainstem, or iontophoretically applied to the dorsal horn of the spinal cord, both Ins P ₅ and Ins P ₆ , but not Ins(l,3,4,5) P ₄ isomers, appear to be potent neural stimulants. These results suggest that the inositol lipid signalling pathways may generate both intracellular and extracellular signals in brain.