Mutations in the () gene cause human intellectual disability, one of the most common cognitive disorders. However, the molecular mechanisms of -related intellectual disability remain poorly understood. We investigated the role of in synaptic function and animal behavior using male mouse and models. knock-out (KO) mice showed normal brain and spine morphology as well as intact synaptic plasticity; however, they also exhibited decreases in synaptic transmission and presynaptic release probability exclusively in excitatory synapses. Presynaptic function was impaired not only by loss of CRBN expression, but also by expression of pathogenic CRBN mutants (human R419X mutant and G552X mutant). We found that the BK channel blockers paxilline and iberiotoxin reversed this decrease in presynaptic release probability in KO mice. In addition, paxilline treatment also restored normal cognitive behavior in KO mice. These results strongly suggest that increased BK channel activity is the pathological mechanism of intellectual disability in mutations. (), a well known target of the immunomodulatory drug thalidomide, was originally identified as a gene that causes human intellectual disability when mutated. However, the molecular mechanisms of CRBN-related intellectual disability remain poorly understood. Based on the idea that synaptic abnormalities are the most common factor in cognitive dysfunction, we monitored the synaptic structure and function of knock-out (KO) animals to identify the molecular mechanisms of intellectual disability. Here, we found that KO animals showed cognitive deficits caused by enhanced BK channel activity and reduced presynaptic glutamate release. Our findings suggest a physiological pathomechanism of the intellectual disability-related gene and will contribute to the development of therapeutic strategies for-related intellectual disability.

Zn2+ is a divalent cation that is essential for many biological activities, as it influences many ion channels and enzymatic activities. Zn2+ can evoke G-protein-coupled receptor signaling via activation of the metabotropic zinc receptor ZnR/GPR39. In spite of evidence suggesting the presence of ZnR/GPR39 in salivary gland cells, there has been no evidence of ZnR/GPR39-mediated modulation of salivary gland function. Here we characterized the role of ZnR/GPR39 in human submandibular gland cells. A 0.25% ZnCl2 solution evoked secretion of unstimulated and stimulated whole saliva in humans. We found that ZnR/GPR39 is expressed in human submandibular glands and HSG cells. Zn2+ increased cytosolic Ca2+ concentration ([Ca2+]i) in a concentration-dependent manner. Muscarinic antagonist had no effect on Zn2+-induced [Ca2+]i increase, which was completely blocked by the phospholipase C-β inhibitor. As with muscarinic agonist, Zn2+ also induced the translocation of aquaporin-5 (AQP-5) to the plasma membrane, which was drastically decreased in ZnR/GPR39-knockdown cells. These data suggest that the metabotropic Zn2+ receptor ZnR/GPR39 can modulate salivary secretion in human submandibular gland cells independent of muscarinic or histamine receptor signaling.

Thalidomide is a widely prescribed immunomodulatory drug (iMiD) for multiple myeloma, but causes reversible memory loss in humans. However, how thalidomide causes cognitive dysfunction at a cellular and molecular level has not been demonstrated. We studied the effect of thalidomide on synaptic functions and cognitive behaviors using a mouse model. Thalidomide led to cognitive deficits in learning behavior in a passive avoidance test and in a novel object recognition test, increased anxiety in an elevated plus maze test, and increased depressive behaviors in a tail suspension test. Interestingly, thalidomide elevated big- or large-conductance, calcium-activated K+ (BK) channel expression in the plasma membrane and BK channel activity in the hippocampus. Thalidomide also increased the paired pulse ratio of excitatory postsynaptic current (EPSC), which suggests a decreased probability of glutamate release. Furthermore, the changes in the paired pulse ratio and in BK channel activity were blocked by paxilline, a BK channel blocker. Finally, we found that thalidomide-induced cognitive dysfunctions were restored by paxilline treatment. These results suggest that thalidomide-mediated BK channel hyperfunction is responsible for the pathological mechanism of thalidomide-associated reversible memory loss.

Zn2+ is divalent cation that is essential for many biological events by affecting various ion channels. Zn2+ can serve G‐protein coupled receptor signaling via activation of metabotropic zinc receptors, ZnR/GPR39. In spite of several evidences of the existence of ZnR/GPR39 in salivary gland cells, there has been no evidence of ZnR/GPR39‐mediated modulation of the salivary gland functions. Here we have characterized the role of ZnR/GPR39 in human submandibular gland cells. Mouth wash with Zn‐containing solution evoked the secretion of unstimulated and stimulated whole saliva in human. We found that ZnR/GPR39 is expressed in the human submandibular glands and HSG cells. Zn2+ increased cytosolic Ca2+ concentration ([Ca2+]i) in a concentration‐dependent manner. Both muscarinic antagonist and histaminergic antagonists did not have any effect on Zn2+‐induced increase [Ca2+]i, which is completely blocked by the inhibitor of phospholipase C‐beta. Like as muscarinic and histaminergic stimulation, Zn2+ induced the translocation of aquaporin‐5 (AQP5) into the plasma membrane. These data suggest that metabotropic zinc receptors can modulate salivary secretion in human submandibular gland cells independently from the muscarinic receptor signaling.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (2017R1A2B4002176 to H.K.P.; 2018R1A5A2024418 to S.Y.C.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.