Inositol Hexakisphosphate Kinase-2 in Cerebellar Granule Cells Regulates Purkinje Cells and Motor Coordination via Protein 4.1N

• Published in: The Journal of neuroscience Vol. 38; no. 34; pp. 7409 - 7419
• Main Authors: Nagpal, Latika, Fu, Chenglai, Snyder, Solomon H
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 22.08.2018
• Subjects: Active Transport, Cell Nucleus; Animals; Biological activity; Brain; Cell Line; Cell morphology; Cell Survival; Cerebellum; Cerebellum - cytology; Cerebellum - enzymology; Cerebellum - physiology; Clonal deletion; Cytology; Cytoskeletal Proteins - physiology; Exploratory Behavior; Female; Granular materials; Granule cells; Inositol; Inositol phosphates; Kinases; Male; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphology; Motor Activity - physiology; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - physiology; Neurons - enzymology; Neurons - physiology; Neuropeptides - physiology; Nuclear transport; Phosphates; Phosphotransferases (Phosphate Group Acceptor) - genetics; Phosphotransferases (Phosphate Group Acceptor) - physiology; Protein 4.1; Protein Binding; Proteins; Psychomotor Performance - physiology; Purkinje cells; Purkinje Cells - enzymology; Purkinje Cells - physiology; Pyrophosphates; Rotarod Performance Test; Synapses; Synapses - physiology; Translocation; synapse; cerebellum; 4.1N; IP6K2
• DOI: 10.1523/jneurosci.1165-18.2018
• ISSN: 0270-6474

Inositol hexakisphosphate kinases (IP6Ks) regulate various biological processes. Among pyrophosphates generated by IP6Ks, diphosphoinositol pentakisphosphate (IP7), and bis-diphosphoinositol tetrakisphosphate have been extensively characterized. IP7 is produced in mammals by a family of inositol hexakisphosphate kinases, IP6K1, IP6K2, and IP6K3, which have distinct biological functions. We report that IP6K2 binds protein 4.1.N with high affinity and specificity. Nuclear translocation of 4.1N, which is required for its principal functions, is dependent on IP6K2. Both of these proteins are highly expressed in granule cells of the cerebellum where their interaction regulates Purkinje cell morphology and cerebellar synapses. The deletion of IP6K2 in male/female mice elicits substantial defects in synaptic influences of granule cells upon Purkinje cells as well as notable impairment of locomotor function. Moreover, the disruption of IP6K2-4.1N interactions impairs cell viability. Thus, IP6K2 and its interaction with 4.1N appear to be major determinants of cerebellar disposition and psychomotor behavior. Inositol phosphates are produced by a family of inositol hexakisphosphate kinases (IP6Ks)-IP6K1, IP6K2, and IP6K3. Of these, the physiological roles of IP6K2 in the brain have been least characterized. In the present study, we report that IP6K2 binds selectively to the neuronal protein 4.1N. Both of these proteins are highly expressed in granule cells of the cerebellum. Using IP6K2 knock-out (KO) mice, we establish that IP6K2-4.1N interactions in granule cells regulate Purkinje cell morphology, the viability of cerebellar neurons, and psychomotor behavior.