The Paul Davies Lab
Activation of γ-aminobutyric acid type A receptors (GABAARs) are responsible for the inhibitory tone of the neuron and impacts the action potential firing frequency. Of particular interest are the GABAAR located outside the synapse, extrasynaptic GABAAR, which mediated tonic inhibition, and are particularly sensitive to general anesthetics and neuroactive steroids.
Fragile X syndrome (FXS) is an autism spectrum disorder, and the most common form of inherited intellectual disability. We are using the mouse model of FXS, (Fmr1 KO mice) to study the role GABAARs have in this disorder. We have discovered that Fmr1 KO mice have deficits in extrasynaptic GABAARs in the dentate gyrus of the hippocampus. Our preliminary data suggest that in Fmr1 KO mice the deficits of tonic inhibition are due to a disruption in normal trafficking of α4-containing extrasynaptic GABAARs. We have recently shown that neuro-active steroids (NAS) exert persistent metabotropic effects on GABAergic inhibition via potentiating the protein kinase C–dependent phosphorylation and membrane insertion of GABAARs containing α4/β3 subunits resulting in a sustained increase in tonic current. We are investigating the ability of NASs to therapeutically reverse the deficits of tonic inhibition in FXS and other neurodevelopmental disorders.
Zinc Activated Channels
The zinc activated channel (ZAC) is a novel cationic channel belonging to the LGIC superfamily. ZAC represents the least understood member of this family mainly because it is absent in mouse and rat genomes. We have recently discovered that ZAC is also activated by copper and protons. Excessive release of these transition metals along with acidification of surrounding environment occurs in pathologies such as ischemia, epilepsy and traumatic brain injury.
ZAC represents a novel therapeutic target for such conditions. Additionally, ZAC is located in the periphery where zinc and copper are known signaling molecules, such as in pancreas and prostate. Healthy prostate plasma normally contains high mM concentrations of zinc but the concentration of zinc drops in cancer. Metastatic prostate cells have low levels of ZAC mRNA expressed. We are currently investigating the functional properties of ZAC in prostate cancer cells.