My laboratory is interested in elucidating the mechanisms by which the activity of ion channels is regulated. In 1952 Hodgkin & Huxley proposed the ionic theory of nerve excitation. At that time, three kinds of ion currents (or channels) were sufficient to explain almost all the properties of nerve conduction. Since then, many more types of ion channels have been discovered. In 1983, the first successful cloning of an ion channel was reported. In 1998, X-ray crystallography revealed the tertiary atomic structure of a K+ channel. This has been an exciting time, when break-through follows break-through.

In collaboration with Yasuko Nakajima's laboratory, my laboratory investigates two types of ion channels: one is the "G protein-coupled inward rectifier K+ channel", and the other type is the family of TRPC channels (transient receptor potential canonical type). Both types of channels play important roles in excitation of neurons and muscles (including cardiac muscles). We investigate these channels using electrophysiological as well as molecular biological methods.

a) Potassium channels

The main focus of the laboratory is to study the GIRK channels (G protein-coupled inward rectifier K+ channels). It is an interesting family of channels: the channel activity is regulated by G proteins, and thus the channel activity is under the control of transmitter substances (such as acetylcholine, amino acid transmitters, etc). When the transmitter substance binds its receptor, the trimeric G protein is dissociated from the receptor, and the ? subunit (G?) and the ?? subunits (G??) are separated from each other. The G?? is the agent, which activates (opens) the GIRK channel (Logothetis et al., Nature, 325, 321; 1987). This channel activation is caused by the direct interaction of G?? with the N- and C-terminus of the GIRK channel (Huang et al., Neuron, 15, 1133;1995. Slesinger et al., Neuron, 15, 1145; 1995). As the result of this interaction, the GIRK channel is activated, resulting in the inhibition of the effectors (neurons, cardiac cells, etc).

The next question is how the GIRK channel is inactivated (closed), resulting in excitation of neurons or cardiac cells. As this has yet to be resolved it is the main research topic of our laboratory.

b) TRPC channels

TRP channels were originally discovered in the Drosophila eye. More recently, several families of channels, belonging to the TRP super-family have been discovered in vertebrates. One of these is the TRPC family (transient receptor potential canonical type). TRPCs are found in almost every kind of brain neuron. When TRPC channels are activated, the channels open, allowing various cations (such as Ca2+, Na+ and K+) to pass through the channel, resulting in cellular excitation.

Channel activation begins with interaction of the transmitter with its receptor. Then, through a cascade of events (signal transduction), the TRPC channels are eventually activated. Our laboratory has been studying this signal transduction. Our previous results (Farkas et al., 1996) indicate that dopamine-containing neurons located in VTA (the ventral tegmental area in the midbrain) display a vigorous activity of non-selective cation channels (Farkas et al., 1996). We observed, by using single-cell reverse transcriptase polymerase chain reaction (RT-PCR), that TRPC6 and TRPC3 are present in dopaminergic neurons of the VTA (we have not yet examined all kinds of TRPCs). Using these dopaminergic neurons as well as cell lines, we are analyzing the signal transduction mechanisms which lead to activation of these TRPC channels.

Lab Members

Selected publications from the Nakajima laboratory:

• Farkas, R.H., Nakajima, S. and Nakajima, Y. (1994) Neurotensin excites basal forebrain cholinergic neurons: ionic and signal transduction mechanisms. Proc. Natl. Acad. Sci. USA 91: 28532857.


• Velimirovic, B. M., Koyano, K., Nakajima, S., and Nakajima, Y. (1995) Opposing mechanisms of regulation of a Gproteincoupled inward rectifier K+ channel in rat brain neurons. Proc. Natl. Acad. Sci. USA 92: 15901594.


• Takano, K., Stanfield, P. R., Nakajima, S., and Nakajima, Y. (1995) Protein kinase Cmediated inhibition of an inward rectifier potassium channel by substance P in nucleus basalis neurons. Neuron 14: 9991008.


• Farkas, R.H., Chien, P.Y., Nakajima, S., and Nakajima, Y. (1996) Properties of a slow nonselective cation conductance modulated by neurotensin and other neurotransmitters in midbrain dopaminergic neurons. J. Neurophysiol. 76: 19681981.


• Chien, P.Y., Farkas, R. H., Nakajima, S., and Nakajima, Y. (1996) Single channel properties of the nonselective cation conductance induced by neurotensin in dopaminergic neurons. Proc. Natl. Acad. Sci. USA 93: 1491714921.


• Albsoul-Younes, A.M., Sternweis, P.M., Zhao, P. Nakata, H., Nakajima, S., Nakajima, Y., and Kozasa, T. (2001) Interaction sites of the G protein subunit with brain G protein-coupled inward rectifier K+channel. J. Biol. Chem., 276: 12712-12717.


• Chen, L., Kawano, T., Bajic, S., Kaziro, Y., Itoh, H., Art, J. L., Nakajima, Y. and Nakajima, S. (2002) A glutamate residue at C-terminus regulates activity of inward rectifier K+ channels: implication for Andersen's syndrome. Proc. Natl. Acad. Sci. U.S.A., 99: 8430-8435.


• Bajic, D., Koike, M., Albsoul-Younes, A. M., Nakajima, S., Nakajima, Y. (2002) Two different inward rectifier potassium channels are targets of transmitter induced modulation of nucleus basalis neurons. Proc. Natl. Acad. Sci., 99: 14494-14499.


• Zhao, Q., Kawano, T., Nakata, H., Nakajima, Y., Nakajima, S., and Kozasa, T. (2003). Interaction of G protein beta subunit with inward rectifier K+ channel Kir3. Mol. Pharmacol. 64, 1085-1091.


• Koike-Tani, M., Collins, J.M., Kawano, T., Zhao, P., Zhao, Q., Kozasa, T., Nakajima, S., and Nakajima, Y. (2005). Signal transduction pathway for the substance P-induced inhibition of Kir3 (GIRK) channel. J. Physiol., 564, 489-500.