By Dean A. Haycock

Special To BioWorld Today

It sounds a little like a lame joke along the lines of "Who's buried in Grant's Tomb?"

What kind of ion can go through a sodium channel? Today the answer is more involved and holds more potential significance for biotechnology and medicine than it did a week ago.

The answer is sodium. And under the right physiological conditions or in the presence of common drugs used to treat heart failure — calcium as well.

The unexpected discovery that sodium channels in heart muscle cells can allow calcium through has implications that go beyond the field of cardiology. Heart muscle cells are excitable cells in the same category as neurons, which also depend on sodium channels to regulate their function. If sodium channels in neurons have similar properties, it could turn out to be a general method of signaling in nervous and sensory systems.

The data supporting the sodium channel's newly discovered promiscuity appears in "Ca2+ Flux Through Promiscuous Cardiac Na+ Channels Slip-Mode Conductance," a paper in the February 13, 1998, issue of Science.

Most of the time, heart muscle cells depend on calcium channels to regulate their contractions, which, in synchronized mass, cause the organ itself to contract and pump blood.

When the outer membranes of heart muscle cells are depolarized, voltage-dependent calcium channels open and allow some calcium ions to enter the cell. These ions bind to receptors on membranes inside the cell which contain yet more stored calcium. These internal calcium stores are released in response to the priming entry of external calcium. The released intracellular free calcium activates the cellular machinery that causes the cell to contract. So far this is all straightforward, textbook material.

But biology often presents apparent paradoxes that reveal its sophistication. In this case, the apparent paradox came from earlier experiments. These showed that when the heart was stimulated by a neurotransmitter, such as adrenaline in response to excitement or stress, internal calcium could be released even if the entry of priming calcium from the outside was blocked.

Scientists explained this by suggesting there was a physical connection, a direct coupling, between the calcium channel on the outside of the heart cell membrane and the interior stores of calcium. After all, this is the arrangement in skeletal muscle cells. Nature conservatively may have maintained the same design as a supplementary or alternative mechanism in heart muscle cells.

That reasonable explanation is seriously challenged by a team led by Jonathan Lederer, professor of physiology at the University of Maryland School of Medicine and head of the department of molecular biology and biophysics at the University of Maryland Medical Biotechnology Center in Baltimore.

Working with rat heart muscle cells, these researchers found it is possible to prevent the release of internal calcium stores seen under conditions when all known entry points for external calcium have been blocked. They did it by blocking sodium channels with the puffer fish poison, tetrodotoxin. This pharmacological tool (the dangerous ingredient that in small quantities titillates the taste buds of Japanese fugu fish fans) is used routinely by scientists to specifically and selectively block sodium channels.

Finding that a sodium channel blocker could stop the release of internal calcium is not what anyone would expect if the internal calcium release resulted from a direct, physical connection with calcium receptors on the outer membrane. The authors described this unexpected feature of sodium channels as "promiscuous permeability" and have named it "slip-mode conductance."

The mechanism can evidently be turned on and off under the control of nerve activity and circulating hormones.

"The finding we've made was completely unexpected and virtually without precedent," Lederer said.

Furthermore, the authors suggested that well-known steroid drugs used to treat heart failure, digoxin and ouabain, can cause calcium to enter cells though the sodium channel. This raises the possibility that slip-mode conductance may be responsible in part for their therapeutic effects.

Because the finding is so new, Lederer could not say exactly how important slip-mode conductance will be in explaining these effects, but suggested it could influence our understanding of both inotropic agents, which increase the strength of contraction of the heart, and anti-arrhythmia agents.

Impact May Go Beyond Heart Drugs

Lederer noted sodium channels are one of the more conservative channels in the animal kingdom. They are found in lower animals, invertebrates, and in different tissues in mammals including humans. There are distinct differences but the similarities are amazing given the genetic diversity of other proteins.

"If it turns out that our findings apply to other tissues as well, and in other creatures, the impact on our understanding of things as divergent as sensory and neural physiology, in all excitable cells, could be enormous," Lederer told BioWorld Today.

Potentially it could represent a new signal transduction system, he said, and it could help to explain processes as diverse as memory encoding and auditory and visual physiology.

"Whenever nerves are active or circulating catecholamines are elevated, this [mechanism] could be called into play," Lederer said.

Recently Lederer's lab has been studying heart failure. They've found that slip-mode conductance works in different animal models of the disease.

"If a drug company could target this particular mechanism, they may be able to come up with a whole new class of agents to increase the strength of contraction of the heart," Lederer said. *

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