Ion Channel Interaction Sheds Light on Epilepsy, Other Neurological Disorders

Newswise — Researchers at the University of Pennsylvania School of Medicine have discovered the mechanism that facilitates how two ion channels collaborate in the control of electrical signals in the brain. The investigators showed that the channels were anchored by a third protein at key locations on the nerve cell surface, allowing them to work together to set the timing and pattern of nerve impulses. They also found that this channel partnership mechanism is present in all vertebrates, but is lacking in invertebrates, suggesting that the coupling of these channels may be essential for the higher abilities of vertebrate brains. The elucidation of this novel interaction should aid efforts to develop new treatments for epileptic seizures, pain, and abnormal muscle movements. They report their findings in the cover article of the March 8 issue of the Journal of Neuroscience.

Sodium and potassium are salt molecules (or ions) found throughout the body. Cells pump extra potassium into their interiors, and pump extra sodium out to the surrounding fluid. Electrical impulses in neurons are created when these ions are allowed to return to their original locations by passing rapidly through channels in nerve cells' outer membranes. Nerve cells possess wire-like extensions, called axons, which initiate these impulses and carry them from one cell to the next.

Penn's Edward Cooper, MD, PhD, Assistant Professor of Neurology, and colleagues, zeroed in on two key regions of nerve axons " the initial segment, where each impulse starts, and the nodes of Ranvier, outlying stations spaced along the axon where the impulse receives an essential electrical boost " to look for the anchoring. Nerve impulses begin after exciting inputs are received by the nerve cell " either from the environment or from other nerve cells in the body. Once adequate input signals have accrued, the movement of sodium into the cell will start a nerve impulse at the axon initial segment. In response to this activity, potassium channels then open, permitting the outward movement of potassium ions.

"The sodium channel opening at the beginning of a nerve impulse is like releasing a compressed spring," Cooper explains. "Without other influences, there is a tendency to keep reverberating, leading to additional, unwanted nerve impulses." Potassium channels have a calming influence on the nerve. "Potassium channels work like shock absorbers, holding back sodium channel activity for a period after each nerve impulse," Cooper continues. Indeed, some patients have mutations in potassium channels that decrease this control, causing excessive nerve firing manifested as epileptic seizures and uncontrolled muscle movements called myokymia and ataxia.

The efficient and speedy passage of nerve impulses along axons is aided by the presence of an insulating cover, known as myelin, which maintains the electrical activity along the entire length of the axon. The nerve impulse is able to skip across the unmyelinated regions of the axon at the nodes of Ranvier, with the help of sodium and potassium channels.

"Each nerve impulse receives a huge boost from the influx of additional sodium ions at these nodes, which allows the signal to be propagated to the next myelinated region of the axon," states Cooper.

In a series of chemical tests on the potassium channels located on the axon initial segment and the nodes of Ranvier, the research team was able to identify a molecular motif that allows both channel types to link to a protein called ankyrin-G. Ankyrin-G, in turn, binds tightly to the nerve cell's cytoskeleton, ensuring the channels' stabilization at the initial segment. The chemical motif identified in the potassium channels was nearly identical to that previously discovered in sodium channels, revealing that the potassium and sodium channels link to the ankyrin-G protein in a similar manner.

"The ankyrin-G-interaction with potassium and sodium channels establishes a unique domain of the cell for initiating the nerve impulse and for boosting the impulse across the nodes of Ranvier," states Cooper.

A comparison of several vertebrate and invertebrate channels led to the discovery that the ankyrin-G interaction is present only in vertebrate species. The chemical motif present in vertebrates did not exist in the potassium channels or sodium channels of invertebrates. This comparison led Cooper and colleagues to realize that the evolutionary split between vertebrates and invertebrates, as demonstrated by this difference in the organization of sodium and potassium channels along neurons, occurred during a similar period in evolutionary history as the appearance of myelin.

"Myelination and the coupling of axonal sodium and potassium channels are fundamental improvements in the nervous system, and these changes are probably necessary for the vertebrate 'life-style'," explains Cooper. "You can only be large and fast-moving if you have a nerve impulse mechanism that is both rapid and highly reliable."

By understanding the relationship between potassium and sodium channels, Cooper and colleagues are working to create new treatments for neurological diseases based on reestablishing the type of nerve-cell impulse control seen in unaffected individuals. In fact, a new drug that acts by increasing the openings of these potassium channels is now undergoing U.S. and international trials for epilepsy, and such agents are also being developed for other neurological and psychiatric conditions.

Study co-authors are Zongming Pan, Tingching Kao, Zsolt Horvath, Julia Lemos, Jai-Yoon Sul, Stephen D. Cranstoun, and Steven S. Scherer, all from Penn, as well as Vann Bennett from Duke University and the Howard Hughes Medical Institute.

This research was funded in part by the National Institutes of Health, the Whitaker Foundation, and the University of Pennsylvania McCabe Foundation. This release and related images can also be seen at: www.uphs.upenn.edu/news.

PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

Penn Health System comprises: its flagship hospital, the Hospital of the University of Pennsylvania, consistently rated one of the nation's "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; Presbyterian Medical Center; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home health care and hospice.