The activity of ion channels underlies every aspect of brain function, and knowledge of their molecular physiology is fundamental to our understanding of how the nervous system works. A recent Science paper, which showed that a potassium ion (K+ ) channel called Kv2.1 can exist in millions of different functional states to regulate action potentials in a graded manner, highlighted just how little we know about the most basic aspects of neuronal cell function.
Research published in the current issue of Cell provides another morsel of knowledge about these exquisite molecular machines. Albright et al have examined the crystal structure of the KtrAB ion transporter, a membrane protein first discovered in the marine bacteriumVibrio alginolyticus, and have provided some evidence of how it functions.
KtrAB consists of two subunits; KtrB is a membrane-spanning subunit containing a number of amino acid residues which allow K+ but not other ions to pass through the central pore, and KtrA is a peripheral subunit attached to the cytoplasmic (or inner) surface of the membrane. The KtrA subunit is an RCK domain (for ‘regulates conduction of K+ ions’) which resembles the RCK domain found in other bacterial K+ channels. Four RCK dimers surround the central pore on the inner surface of the cell membrane, and keep it in its proper place. The interfaces between adjacent RCK domains form pockets into which calcium ions (Ca2+) enter; binding of Ca2+ to the pockets in the RCK domains causes opening of the pore.
In bacteria, KtrAB is known to be involved, among other things, in osmoadaptation, the response to a high salt concentration in the surrounding environment, which causes water to leave the cells rapidly. The initial phase of the bacterial cell response involves an uptake of K+, which is mediated by KtrAB.
Albright and his colleagues have established that KtrAB has an octomeric ring conformation, and that opening and closing of the central pore requires an interaction between the A and B subunits. They also propose a model for its gating mechanism, which is illustrated in the animated GIF above. Flexible RCK dimers in closed and open conformation are shown shown in green and red, respectively; Ca2+ ions are shown as grey circles; and the conformational changes of the domains that occur during channel opening are represented in light brown. (Refresh the page to view the animation again.)
The authors suggest that their findings can be generalized to the functioning of other K+ transporters, including the K+ channels found in the nervous systems of all organisms. A greater understanding of ion channel function may one day lead to treatments for the so-called ion channelopathies, a variety of conditions, ranging from epilepsy and migraine to cardiac arrhythmia, in which abberant ion channel function has been implicated.