Inositol hexakisphosphate kinase-1 regulates behavioral responses via GSK3 signaling pathways

Abstract

Glycogen synthase kinase 3 (GSK3), a prominent enzyme in carbohydrate metabolism, also has a major role in brain function. It is physiologically regulated by the kinase Akt, which phosphorylates GSK3 to inhibit catalytic activity. Inositol hexakisphosphate-1 (IP6K1) generates the inositol pyrophosphate diphosphoinositol pentakisphosphate (IP7), which physiologically inhibits Akt leading to enhanced GSK3 activity. We report that IP6K1 binds and stimulates GSK3 enzymatic activity in a non-catalytic fashion. Physiological relevance is evident in the inhibition of GSK3 activity in the brains of IP6K1-deleted mice. Behavioral alterations of IP6K1 knockout mice resemble those of GSK3 mutants. Accordingly, modulation of IP6K1-GSK3β interaction may exert beneficial effects in psychiatric disorders involving GSK3.

Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

“…Finally, an imbalance in IP levels in the human body, as well as genetic deletion of IP6K enzymes in mouse models, has been implicated in a number of psychiatric and neurodegenerative diseases (47)(48)(49)(50). It will be important to gain insights into the structural mechanism underlying high-affinity 5-IP 7 binding and inhibition of the Syt1 protein.…”

Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis

“…IP6Ks also regulate cellular functions via distinct mechanisms that do not require catalytic activity (49)(50)(51)(52). For instance, IP6K1 interacts with glycogen synthase kinase and perilipin to modulate their cellular functions (49,52).…”

“…IP6 regulates cellular processes by binding to its protein targets (44), whereas 5-IP7 modulates its targets by binding or by pyrophosphorylation (42,(45)(46)(47)(48). IP6Ks also regulate cellular functions via distinct mechanisms that do not require catalytic activity (49)(50)(51)(52). For instance, IP6K1 interacts with glycogen synthase kinase and perilipin to modulate their cellular functions (49,52).…”

“…Deletion of Ip6k1 significantly influences various aspects of mouse biology, and thus, targeting this isoform is expected to be beneficial in obesity, T2D (45,58,69,70), innate immunity (59), thromboembolism (71), cancer metastasis (56), and psychiatric and neurodegenerative diseases (49). Ip6k1 KO mice are protected against high-fat diet-induced (HFD-induced) weight gain, insulin resistance, and fatty liver (58).…”

“…Thus, it is conceivable that in the presence of IP6K1, IP6 is converted to either 5-IP7 or IP5*, which neutralizes IP6-mediated AMPK activation. To test this, we used purified catalytically active and inactive versions of recombinant human IP6K1 (49). Catalytically active IP6K1 potently decreases IP6's stimulatory action, whereas the inactive IP6K1 is largely ineffective ( Figure 7E).…”