Fat may affect electrical impulses in brain, heart

April 14, 2005 -- Fatty molecules may modulate the electrical characteristics of nerve and heart cells by regulating the properties of key cell pores, according to research conducted at Washington University School of Medicine in St. Louis.

The findings suggest a novel mechanism in which dietary fat can attach directly to proteins that regulate bioelectricity. This can affect the performance of nerve and heart cells, with potentially broad-ranging health implications.

The researchers report in the April 26 issue of the Proceedings of the National Academy of Sciences that the proteins in specific electrically responsive cell pores—voltage-sensing potassium channels—can bind to molecules of palmitate. Palmitate is a saturated fatty acid previously linked to "hardening" of the arteries and obesity and is a common fat in unhealthy diets.

"In effect, the attachment of palmitate makes these potassium channels, called Kv1.1 channels, open more easily, and this can influence the transmission of electrical impulses along nerve cells and the contraction of heart muscle cells," says senior author Richard Gross, M.D., Ph.D., professor of medicine, of chemistry and of molecular biology and pharmacology and director of the Division of Bioorganic Chemistry and Molecular Pharmacology.

Potassium channels are among the most important cell channels used for propagating electrical signals in nerve and heart muscle. Their protein units form pores that permeate the outer wall or membrane of the cell and selectively allow the passage of potassium ions, which are essential components of cell signaling systems.

Like a meter that measures charge in a battery, a Kv1.1 channel senses the amount of voltage between the interior and exterior of cells and can open and close in response to voltage changes.

Because they are embedded in the cell membrane, Kv1.1 channels are tightly surrounded by the fatty molecules of the membrane, which line up next to each other to create a stable structure.

"We think the attached palmitate molecule causes a defect in the close, regular packing of the membrane's fatty molecules around the Kv1.1 channel, because the palmitate has a different shape," Gross says. "This shape loosens the membrane packing, changes the movement of the channel protein and alters the voltage needed for it to open or close."

The researchers identified the specific site or amino acid in the Kv1.1 protein units that palmitate most often links to. They discovered that a short sequence of amino acids on either side of the attachment site is found in several other proteins as well, arguing for an evolutionarily conserved function for this amino acid sequence.

Most strikingly, five of six amino acids adjacent to the attachment site matched a site where palmitate is known to attach to CD36, an abundant protein vital for moving fatty molecules through the membrane into cells.

"When we see that molecules as widespread, as important and as different from each other as CD36 and Kv1.1 are linked to palmitate at the same sequence—that's nature sending us a message," Gross says. "It's possible that this palmitate attachment site has been used throughout evolution to fulfill functions involving fatty molecules."

Future investigations will seek to further characterize the electrical properties conferred by the addition of palmitate to Kv1.1. The research team will also begin studies with mice to determine the effects of dietary fats on palmitate attachment and the electrical characteristics of cells.

"We want to find out if a connection exists between dietary fats, the attachment of palmitate to proteins and health," Gross says. "In obesity or in cellular lipotoxicity, you exceed cells' capacity to handle fatty acids. Accumulation of fatty acids can lead to an increase in alterations like palmitate attachment, not only in Kv1.1, but in dozens or even hundreds of other proteins. That possibly explains some of the many types of damage that result from having too high of a fatty acid burden."

Gubitosi-Klug RA, Mancuso DJ, Gross RW. The human Kv1.1 channel is palmitoylated, modulating voltage sensing: Identification of a palmitoylation consensus sequence. Proceedings of the National Academy of Sciences. 2005;102(17): 5964-5968.

Funding from the National Institutes of Health supported this research.

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.