nerve cells electrical characteristics modulated by fatty molecules

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Fat may affect electrical impulses in brain, heart

15 Apr 2005 Medical News Today

Molecules attach to proteins that regulate bioelectricity -

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

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.

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