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Professor Yasushi Okamura

Integrative Physiology

The Department of Physiology consists of the Laboratory of Brain Physiology and Laboratory of Integrative Physiology headed by professors Kitazawa and Okamura, respectively. Laboratory of Integrative Physiology is descendant of the Laboratory of Physiology II established in 1931.

Elucidating the mechanism of molecules responsible for transmitting electrical signals in the body and measuring cellular electrical signal

Electric signals enable important functions in our body that are necessary for survival, such as the secretion of small molecules from cells to control communication between neurons and contraction of muscles. Various membrane proteins, such as ion channels and transporters, precisely regulate these functions and are important molecular targets for drug discovery (e.g. anti-hypertension and diabetes drugs).

The frequency of electric signals depends on the function needed. For instance, the action potential in neurons and skeletal muscles occurs within milliseconds, while in the gastrointestinal tract, it occurs more slowly (within seconds). In this way, an appropriate electric signal is produced at the correct location depending on the biological function. In recent years, advances in genomic and structural biology have elucidated the molecular mechanisms underlying the machinery involved in generating electrical signals.

The lab focuses on the function of a sensor molecule called voltage-sensing phosphatase (VSP), which detects changes in membrane potential. VSP is a hybrid molecule that has an enzymatic domain and an ion channel with a sensor domain. The sensor domain has a structure similar to that of typical ion channels, but does not have an opening for ions to pass through. Therefore, when a membrane potential signal occurs, instead of a pore opening, VSP is activated. VSP has unique characteristics and is structurally similar to PTEN, a tumor suppressor gene. When the membrane potential depolarizes, the enzyme is activated to dephosphorylate inositol phospholipid, a constituent of the dual lipid membrane and an intracellular signaling molecule.

Voltage sensor domain only protein (VSOP / Hv1) is a voltage-gated proton channel and has two roles consisting of membrane potential sensing and proton conduction. The molecular weight of VSOP is the smallest of the ion channel proteins encoded in the mammalian genome. Unlike ordinary ion channels in which multiple homologous proteins aggregate to form a channel for ions to pass through, monomeric VSOP permits ions to pass (Figure 1).

Figure 1

Using a conceptual understanding of these potential sensor proteins as a starting point, the lab aims to further elucidate the overall mechanism of ion channels, which is the basis of various physiological functions. To this end, electrophysiological assays are being used to measure structural changes with fluorescent molecules to analyze the protein structure (Figure 2). Genetically modified animals such as mice and zebrafish are being used to study the function of blood cells and microglia in the brain. Furthermore, the lab is developing new technologies to measure and manipulate electrical activity in living organisms. Lastly, the lab is conducting fundamental research using animal models to develop and improve artificial retina.

Figure 2