β subunit of VDCC act as platform for various synaptic proteins to regulate neuronal function.

At the active zone of a synapse, VDCC rapidly transduces electrical signal to chemical signal by mediating Ca2+ influx in response to change in membrane potential that ultimately results in neurotransmitter release. High voltage dependent calcium channels (VDCC) consist of α1, α2/δ, β and γ subunit. The α1 subunit is a pore forming 2000 amino acid transmembrane protein that is composed of four domains each of which contains six transmembrane regions. Importantly, the β subunit binds to the cytosolic domain of the α1 subunit and plays an essential role in channel activation as well as transportation of α1 subunit from the ER to the plasmamembrane (Mori et al., 1991; Pragnell et al., 1994; Bichet et al., 2000).

Our laboratory focuses on identification of synaptic proteins that interact with the β subunit. Fast synaptic transmission is made possible by a tight spatial coupling between VDCC and the synaptic vesicle. We have discovered that this coupling is modulated by an interaction between the β subunit with synaptic proteins RIM family. We also found that an interaction of the β subunit with the synaptic proteins RIM family, CAST and bassoon modulate the Ca2+ influx through VDCC (Kiyonaka et al., 2007; Nishimune et al., 2012; Kiyonaka et al., 2012).

Most recently, in collaboration with Dr. Michel De Waard`s laboratory, we have discovered an additional role of β subunit as a gene regulatory factor in the nucleus. In neuron, membrane depolarization induces nuclear translocation of β subunit via association with phosphatase to directly regulate the expression of genes involved in production of neurotransmitter. A mutation that disrupts the nuclear translocation of β subunit is implicated in juvenile epilepsy (Tadmouri et al., 2012).

In total, our finding suggests β subunit of VDCC act as platform for various synaptic proteins to modulate broad range of neuronal function from neurotransmission to gene expression.

TRP channels sense the cellular redox status and orchestrate physiological response

TRP channels are non selective cation channels that are activated by diverse chemical and physical stimuli such as pH, temperature, oxidative stress, osmotic pressure and mechanical stress. Due to this unique property, TRP channels are considered as biological sensors to signal environmental changes from outside to the inside of cell.

Our laboratory leads the field of redox biology by identifying redox-sensitive TRP channels. We found that TRPM2, the first TRP channel to be identified as having redox sensitivity, is activated by reactive oxygen species and mediates a calcium influx that aggravates inflammation (Hara et al., 2002; Yamamoto et al., 2008). In addition, we found that TRPC5, TRPV1, TRPV3 and TRPV4 are activated by nitric oxide (NO) (Yoshida et al., 2006). Most recently, we found TRPA1 activation by hyperoxia and hypoxia in vagal and sensory neurons (Takahashi et al., 2011).

Molecular Cloning

Our laboratory is actively exploring new genes in the genome and has discovered VDCC (P/Q type channel), TRPC5 and TRPC7 gene (Mori et al., 1991; Okada et al., 1998; Okada et al., 1999)

Development of novel pharmaceutical compounds that target calcium channels

The research and treatment of diseases involving various calcium channels are hampered by lack of selective inhibitors. In order to address this problem, we are actively seeking for compounds that inhibit these calcium channels with sufficient selectivity. We have identified a direct and selective inhibitor of TRPC3 channel Pyrozole 3 (Kiyonaka et al., 2009).