Background: Activation of TRPC4/5 channels is mediated by GPCR activation. Results: TRPC4/5 was activated by the G␣ i/o -coupled receptor and the G␣ i protein, which interacted directly with each other. Conclusion: G␣ i proteins play an essential role as novel activators of TRPC4/5. Significance: Our findings provide new insights into the activation mechanism of inhibitory G␣ proteins.

Aberrant glutathione or Ca(2+) homeostasis due to oxidative stress is associated with the pathogenesis of neurodegenerative disorders. The Ca(2+)-permeable transient receptor potential cation (TRPC) channel is predominantly expressed in the brain, which is sensitive to oxidative stress. However, the role of the TRPC channel in neurodegeneration is not known. Here, we report a mechanism of TRPC5 activation by oxidants and the effect of glutathionylated TRPC5 on striatal neurons in Huntington's disease. Intracellular oxidized glutathione leads to TRPC5 activation via TRPC5 S-glutathionylation at Cys176/Cys178 residues. The oxidized glutathione-activated TRPC5-like current results in a sustained increase in cytosolic Ca(2+), activated calmodulin-dependent protein kinase and the calpain-caspase pathway, ultimately inducing striatal neuronal cell death. We observed an abnormal glutathione pool indicative of an oxidized state in the striatum of Huntington's disease transgenic (YAC128) mice. Increased levels of endogenous TRPC5 S-glutathionylation were observed in the striatum in both transgenic mice and patients with Huntington's disease. Both knockdown and inhibition of TRPC5 significantly attenuated oxidation-induced striatal neuronal cell death. Moreover, a TRPC5 blocker improved rearing behaviour in Huntington's disease transgenic mice and motor behavioural symptoms in littermate control mice by increasing striatal neuron survival. Notably, low levels of TRPC1 increased the formation of TRPC5 homotetramer, a highly Ca(2+)-permeable channel, and stimulated Ca(2+)-dependent apoptosis in Huntington's disease cells (STHdh(Q111/111)). Taken together, these novel findings indicate that increased TRPC5 S-glutathionylation by oxidative stress and decreased TRPC1 expression contribute to neuronal damage in the striatum and may underlie neurodegeneration in Huntington's disease.

GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466-478.

Oxidative stress is a key mediator of neuronal death in acute brain injuries, such as epilepsy, trauma, and stroke. Although it is accompanied by diverse cellular changes, increases in levels of intracellular zinc ion (Zn) and calcium ion (Ca) may play a critical causative role in oxidative neuronal death. However, the mechanistic link between Zn and Ca dyshomeostasis in neurons during oxidative stress is not well-understood. Here, we show that the exposure of cortical neurons to HO led to a zinc-triggered calcium influx, which resulted in neuronal death. The cyclin-dependent kinase inhibitor, NU6027, inhibited HO-induced Ca increases and subsequent cell death in cortical neurons, without affecting the early increase in Zn. Therefore, we attempted to identify the zinc-regulated Ca pathway that was inhibited by NU6027. The expression profile in cortical neurons identified transient receptor potential cation channel 5 (TRPC5) as a candidate that is known to involve in the generation of epileptiform burst firing and epileptic neuronal death (Phelan KD et al. 2012a; Phelan KD et al. 2013b). NU6027 inhibited basal and zinc-augmented TRPC5 currents in TRPC5-overexpressing HEK293 cells. Consistently, cortical neurons from TRPC5 knockout mice were highly resistant to HO-induced death. Moreover, NU6027 is neuroprotective in kainate-treated epileptic rats. Our results demonstrate that TRPC5 is a novel therapeutic target against oxidative neuronal injury in prolonged seizures and that NU6027 is a potent inhibitor of TRPC5.

Transient receptor potential melastatin 7 (TRPM7) is a member of the melastatin-related subfamily and contains a channel and a kinase domain. TRPM7 is known to be associated with cell proliferation, survival, and development. It is ubiquitously expressed, highly permeable to Mg2+ and Ca2+, and its channel activity is negatively regulated by free Mg2+ and Mg-complexed nucleotides. Recent studies have investigated the relationships between TRPM7 and a number of diseases. TRPM7 regulates cell proliferation in several cancers, and is associated with ischemic cell death and vascular smooth muscle cell (VSMC) function. This review discusses the physiologic and pathophysiologic functions and significance of TRPM7 in several diseases.