Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is the neuronal isoform of ITPKs and exhibits both actin bundling and InsP3kinase activity. In addition to neurons, ITPKA is ectopically expressed in tumor cells, where its oncogenic activity increases tumor cell malignancy. This raise the question, if inhibition of ITPKA could reduce oncogenic activity. However, prior to developing ITPKA specific inhibitors for treatment of cancer patients, it has to be excluded that ITPKA exhibits essential functions in non-tumor cells.
In this new study, a team of scientists investigated the physiological relevance of ITPKA. In order to analyze the effect of global ITPKA deficiency, a systemic phenotyping of Itpka deficient mice at the German Mouse Clinic was performed. The results were published recently in “Neuroscience letters.”
In addition to the published data about the role of ITPKA in neurons of the CNS, this kinase was involved in the regulation of nociceptive pathways, sensorimotor gating and motor learning. Itpka deficient mice reacted faster to a hotplate, prepulse inhibition was impaired and the accelerating rotarod test showed decreased latency to fall.
Interestingly, analysis of extracerebral functions revealed significantly reduced glucose, lactate, and triglyceride plasma concentrations in Itpka deficient mice that hints to metabolic disturbance. Based on this finding, expression of ITPKA was analyzed in extracerebral tissues and the highest level was found in the small intestine. However, functional studies on CaCo-2 control and ITPKA depleted cells showed that although ITPKA controls the calcium signaling in CaCo-2 cells, its depletion did not affect uptake of glucose or triglycerides.
The results of the study indicate that Itpka deficiency in mice leads to specific CNS and subtle metabolic phenotypes. These findings have to be taken into account when developing selective ITPKA inhibitors to block the oncogenic activity of ITPKA.
Christine Blechner; Lore Becker; Helmut Fuchs; Birgit Rathkolb; Cornelia Prehn; Thure Adler; Julia Calzada-Wack; Lillian Garrett; Valerie Gailus-Durner; Martin Hrabe de Angelis; Fabio Morellini; Susanne Conrad; Sabine Hoelter; Eckhard Wolf; Thomas Klopstock; Jerzy Adamski; Dirk Busch; Michael Schmeisser; Sabine Windhorst
Physiological relevance of the neuronal isoform of inositol-1,4,5-trisphosphate 3-kinases in mice [published online ahead of print, 2020 Jun 25]. Neurosci Lett. 2020;735:135206. doi:10.1016/j.neulet.2020.135206