title: Hint1 knockout results in a compromised activation of protein kinase C gamma in the brain.
abstract: Previous studies have implicated a role of the histidine triad nucleotide-binding protein 1 (Hint1) in the pathogenesis of schizophrenia. Protein kinase C gamma (PKCγ) could be potentially involved in the Hint1-implicated pathogenesis since PKCγ was identified as a Hint1 interacting protein. Recently, a debate was brought forward from the understanding how Hint1 affects the expression and activity of PKCγ in the brain. In the present study, we use Hint1 knockout mice and biochemical analysis to define the effect of Hint1 on protein PKCγ. Our data reveal that Hint1-deficiency in mouse brains led to increased protein levels of PKCγ in the cortex and hippocampus, the striatum and thalamus and amygdala. Without stimulation, PKCγ protein in Hint1-deficient brain displayed a basal activity that was reflected by control-leveled phosphorylations of PKCγ T514 and T674 at its kinase domain. Upon psycho-stimulation, both sites of PKCγ T514 and T674 were activated in these brain structures via phosphorylation; however, the phosphorylation level at the site of PKCγ T674 apparently attenuated in Hint1-deficient mice compared to wild-type control. Thus, we conclude that Hint1 deficiency leads to an increased protein level of PKCγ in the brain and a compromised activation response of PKCγ upon stimulation. These findings suggest an inhibitory role of Hint1 on the protein PKCγ in the brain and an impaired PKCγ-mediated phosphorylation signal in Hint1-deficient neuron.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA. Electronic address: zhangfan100@hotmail.com.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Zhenfei
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA. Electronic address: jwang@rx.umaryland.edu.
authors.forename: Jia Bei
authors.initials: JB
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D008297:Male; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; C489275:Hint1 protein, mouse; D009419:Nerve Tissue Proteins; C087857:protein kinase C gamma; D011493:Protein Kinase C; D003913:Dextroamphetamine
keywords: Hint1; Phosphorylation activation; Protein abundance; Protein kinase C gamma