How electrical signals are conducted through nerve cells has been understood with some detail in the last fifty years, after the seminal work of Hodgkin and Huxley, which earned them a Nobel Prize in 1963. After 40 years, another study is appreciated in the scientific community as the end of one era and the beginning of another one.
Cells, body’s building blocks, are bound by membranes that are impermeable to ions, atoms that carry positive or negative charge. Nerve cells are specialized for having very long arms that can carry electric potentials on their membranes for very long distances. The electric potential (voltage difference) is the result of unequal number of charges across the inside and outside of the cell membrane. Hodgkin and Huxley explained the movement of the electric potential on the membranes by the selective opening of ion channels, proteins embedded in membranes to allow the passage of certain ions. As channels are opened in one part of the nerve cell to allow an electrical potential change, the neighboring stretches somehow sense the change in voltage and open their channels as well. The propagation of the electric potential depends on the fast sensing, opening and closing of these channels. The molecular details of these voltage-gated channels have been somewhat obscure; however important properties have been determined using methods pioneered by Hodgkin and Huxley, generally dubbed electrophysiology, the study of biological material using electrical methods. Scientists
have imagined channel proteins as many helices running through the membrane, some of which could be pulled to the inside or outside of the cell depending on the voltage across the
membrane. Movement of these helices across the membrane could open channels for potassium or sodium. Finally in May 2003, Roderick Mackinnon’s research group at Rockefeller University has published the three-dimensional atomic structure of a voltage-gated potassium channel. MacKinnon also received the Nobel Prize in 2003 for the first potassium channel structure, which explained the selectivity of a potassium channel for allowing only potassium ions to pass, but nothing else.
MacKinnon is a mixed structural biologist and electrophysiologist. His group has isolated potassium channel molecules from membranes, and tested them for strict functionality as it has been observed that protein molecules isolated out of their natural environments may lose their activities and chemical properties. The next step of their study was to crystallize the channel molecules-much like forming salt crystals-and diffract x-rays through the aligned molecules in the lattice of their crystals. These diffraction patterns are mathematically solved to give atomic positions of electrons, hence atoms, in the protein crystal. Several research groups failed at this step, since purified potassium channels never formed crystals, as flexible protein molecules are unlikely to form crystals. Here, MacKinnon cleverly used antibodies they developed specifically against the channel. These antibodies, used radically differently than they are in nature, overcame the flexibility of the voltage-sensing regions of the channel, by binding to the channel and fixing it to a specific conformation. The ordered channel crystallized and gave the structure of the potassium channel and the antibody bound to it.
The structure of the channel consists mostly of helices, which in the center surround a potassium-conduction pore, and “voltage-sensing paddles” in the periphery. When the gate is closed, the helical paddles lay parallel at the cellular side of the membrane. Gate opening only happens when the paddles are pulled through the membrane to the outer side as voltage pulls the positive charge of the paddles to the outside (see figure). Now, it looks like 50 years of data collected by electrophysiologists and biochemists can be explained coherently (such as the observed 14 positive charges residing on the paddles moving through the membrane). As is usual with such discoveries, many new questions are asked, such as how the charged paddles can go through the oily, highly uncharged membranes. There are also valid scientific objections, such as the antibody distorting the potassium channel structure. However, this is one of those bright moments in any field of research, when researchers go over the threshold of collection of enough observations to discovery and understanding.
Jiang, Y., Lee, A., Chen, J., Ruta, V., Cadene, M., Chait, B.T., MacKinnon, R., Nature 423, 33-41 (2003).
Jiang, Y., Ruta, V., Chen, J., Lee, A., MacKinnon, R., Nature 423, 42-48 (2003).
Sigworth, F.J., Nature 423, 21-22 (2003).