The Center for the Investigation of Membrane Excitability Disorders

Jeanne M. Nerbonne, Ph.D., and Colin G. Nichols, Ph.D., Directors

Diseases as wide ranging as cystic fibrosis, epilepsy, migraine, abnormal heart rhythm and type 2 diabetes have something in common. They are linked to flaws in molecular structures called ion channels, which move charged particles into and out of cells. The Center for the Investigation of Membrane Excitability Disorders (CIMED) focuses on gaining a better understanding of ion channels to aid in the development of new medical approaches for these kinds of disorders.

"CIMED will pull together scientists from different disciplines with a fundamental interest in ion channels," says co-director Jeanne M. Nerbonne, Ph.D., the Alumni Endowed Professor of Molecular Biology and Pharmacology. "We will particularly emphasize how inherited and acquired derangements in the expression or the functioning of ion channels are implicated in disease."

Ion channels are pores in the outer membranes of cells. More than mere openings, these pores are actually specialized structures that select particular electrically charged molecules, or ions, and pass them through the cell membrane. This process is an important aspect of nerve communication, muscle contraction, hormone secretion, cell division and immune function, to name a few.

Different ion channels exist to handle calcium, sodium, potassium and chloride ions. Because of the electrical charge that these ions have, their movement across cell membranes creates electrical activity — membrane excitation — that controls key events within living cells.

"All biologists know that nerve signals are electrical signals," says co-director Colin G. Nichols, Ph.D., the Carl Cori Professor of Cell Biology and Physiology. "Most also know that electric signals drive the beating of the heart and muscle contraction. But there is much less awareness that all organs of the body have electric signals that control certain functions."

Now recognition is growing about the central role of membrane excitability, while at the same time genome sequencing projects are uncovering mutations in genes that encode ion channels. "It's becoming clear that many diseases are linked to genetic mutations and dysfunction of the proteins that make up ion channels, even in cells not generally thought of as excitable," Nerbonne says.

Mutations in ion channel genes are linked to congenital cardiac rhythm disturbances such as the long QT syndromes and atrial fibrillation, as well as to inherited neurological disorders including epilepsies and ataxias, and to sudden infant death syndrome. Recently, work in the Nichols laboratory has led directly to the discovery that mutations in potassium channels are responsible for neonatal diabetes.

Because a particular type of ion channel can be located in many different tissues, single gene mutations can lead to complex diseases that affect multiple organ systems. The rare inherited disorders Timothy Syndrome and Andersen's Syndrome, for example, are caused by single mutations in ion channel genes, but these mutations affect the heart, skeletal muscle and nervous systems.

"The researchers in CIMED will use a variety of approaches to study membrane excitability," Nichols says. "The central point we come from is the biophysical and electrical behavior of the channels themselves. In studying electrophysiology — that is, measuring biological currents and voltages — we will look multiple levels, from single channels in artificial membranes to ion channel function in animals."

Nichols and Nerbonne say they also plan to focus on gene expression — finding which cells or organs express specific ion channel genes and what factors control the gene expression. They are also interested in making use of imaging techniques — being able to look at these ion channel proteins to see how they move and what they interact with.

Combining clinical expertise with advanced tools in biochemistry, electrophysiology, imaging and genomics, CIMED will be in a position to make important advances in understanding disease mechanisms and in translating these insights into improved treatments and therapeutics.

"I also think researchers in many fields increasingly will discover that membrane excitability is a component of what they are investigating," Nichols says. "Previously, such researchers would have to make ad hoc interactions with labs like ours to work on that question. But with CIMED, we are hoping to create a central resource they can rely on."

"That's how we got started on this idea," Nerbonne says. "If you have 'grown up' as an electrophysiologist, you have no doubt that membrane excitability is important. But the broadening realization of its importance means there's a huge opportunity at an institution like ours to bring new ideas and approaches to areas where they haven't yet been utilized."