How Overactive Membrane Ion Channels Influence Asthma and Other Disorders

It May Be Time To Change: Treat Excitation Not Inflammation

At first glance, asthma and epilepsy don’t seem to have much in common: one is a neurological disorder, the other a breathing problem. But according to a new model of asthma by Ba Hoang, MD, PhD, Stephen Levine, PhD and colleagues, published in Medical Hypotheses in 2006, asthma symptoms may be viewed as a hyper-excitability condition of the airway that is actually kindled in a manner similar to epilepsy, and can be triggered by a variety of endogenous and environmental factors.

This new model goes beyond descriptive studies of inflammatory immune mediators or abnormalities in smooth muscle function, and looks deeper—at dysfunction in the electrical potential of the cell membrane. If this view proves correct, it might provide a novel way of explaining asthma, as well as suggesting new therapeutic approaches. It also may offer insight into the runaway cascade of ill health we see in other chronic conditions.

Chronic membrane hyper-excitability leads to its exact opposite, depletion of cellular energy that results in pathology. By reversing cell membrane hyper- excitability, Ba and colleagues suggest, we can reverse chronic inflammation and pathology, and restore cellular health. We already know that ion channels exist in the brain, that when hyperactive can cause neurons to fire abnormally, resulting in, for instance, the seizures of epilepsy. It turns out that these ion channels also exist in the lungs. In fact, a receptor once thought only to belong to the central nervous system—called the N-methyl-D-aspartate (NMDA) glutamate receptor—is present in our lungs and bronchial tubes.

The electrical potential of a cell membrane is a fascinating topic, one that bridges both biology and physics. All cell membranes have electrical potential, activated through ion channels that open and close constantly, letting thousands to millions of ions diffuse down their electrochemical gradient. When a channel switches between a conducting and nonconducting state, this is called gating. These gated channels can be responsive to sodium, potassium, magnesium, chloride, and other molecules. The electrical signal spreads rapidly over the cell and allows almost instantaneous communication to occur. Membrane channels can bind or reject an ion in the most astoundingly brief time intervals—10 to 100 nanoseconds. A nanosecond is only one-billionth of a second.

According to Ba & Levine, sodium voltage-gated channels may be involved in the pathogenesis of asthma, and may offer us a deeper understanding of this condition that will help us ultimately provide novel, therapeutic interventions to modify the disease or even achieve a cure.

Salt of the Earth: How Sodium and Glutamate Trigger Asthma

Sodium-gated ion channels may play a major role in membrane excitability. An influx of sodium is linked to release of the acetylcholine, which results in smooth muscle contraction. Not surprisingly, two sodium channel blockers—lidocaine and phenytoin—have been proven already to be effective anti-asthma agents. Lidocaine is a local anesthetic, anticonvulsive and antiarrhythmic agent that works primarily by blocking sodium channels and decreasing membrane excitability. Phenytoin is an anticonvulsant and cardiac depressant used to treat epilepsy and arrhythmias. It blocks repetitive firing of neurons by acting on sensitive sodium channels.

Ba and colleagues believe that sodium channels contribute to asthma by modulating the neurotransmitters acetylcholine, glutamate, and GABA. In particular, they believe that asthma occurs as a result of hyperactivity of the NMDA glutamate receptors in the airways. Glutamate is an excitotoxin and its action in rat lungs looks very much like asthma. Glutamate increases the release of acetylcholine. Excess glutamate is well known to be linked to loss of neuronal function in diseases as wide ranging as Huntington's, Parkinson’s, ALS, and epilepsy. Excess glutamate has also been shown to directly lead to cell proliferation via inflammation. GABA, in turn, is the main inhibitory neurotransmitter, and like glutamate is also found in the lung. GABA agonists (chemicals that increase activation of GABA receptors) inhibit smooth muscle contraction, anaphylactic bronchospasm, and cough. That means that, just as in the brain, glutamate (excitatory) and GABA (calming and inhibitory) are in flux and move in tandem, so they do in the lung.

The hypothesis: the cell membrane is induced into a hyper-excitable state via sodium ion channels, which activates the NMDA glutamate receptor. When it is overactive this provokes hyperexcitability, leading to cell injury and cellular proliferation. In the short run this triggers reversible bronchoconstriction and inflammation. In chronic cases, this might lead to thickening of the airway wall and inflammation. This excitotoxic process does much of its damage by triggering excessive production of inflammatory chemicals, and creating a constant high-energy demand and drain that ultimately depletes the cell.

This hypothesis may explain why some asthma is so refractory and severe, and unresponsive to beta-agonists or steroids.

Are We Treating Inflammation or Excitation?

Ba and colleagues believe we should be using an excitatory modulator to calm overexcited cells that may be at the root of asthma. The nutrients magnesium, taurine and glycine, and the ketogenic (high protein) diet are known to be beneficial in epilepsy; for the same reason, they may benefit asthmatics. Magnesium may work by inhibiting calcium, since it has been shown that the excitotoxic action of glutamate may often involve abnormal uptake or intracellular mobilization of calcium ions.

The herb Sophora flavescens may be an effective treatment for asthma. Two alkaloids found in the herb—matrine and oxymatrine—are excitatory modulators. Recent research suggests Sophora may neutralize excessive build-up of glutamate and reduce the sensitivity of the excitatory NMDA receptor, potentially inhibiting an important cause of membrane hyper-excitability. The alkaloids in this herb have been found to inhibit glutamate action in a study in crayfish. So perhaps when we think of asthma, we should not think of calming inflammation, but of looking deeper, and calming hyper-excitability of the cell membrane itself, providing an effective, safe treatment that may even allow the cells to heal over time.

What About Ion Channels and Cancer?

Could the pathogenic changes and uncontrolled proliferation of cancer be linked to cellular hyper-excitability mediated by voltage-gated ion channels? This is what Ba and colleagues suggest in a 2007 paper in the European Journal of Cancer Prevention. In fact, notes Ba, “It has been reported that glutamate antagonists at…glutamate receptor/ion channel complexes limit growth of human cancers….the antiproliferative effect of glutamate antagonists is calcium dependent…the proliferative effect of cancer varies directly with the intracellular calcium levels.” Expression of a specific NMDA receptor and its involvement in cellular proliferation is well known in tumors of neuronal tissues, such as glioma and neuroblastoma. Excessive expression of this receptor has also been seen in prostate, breast and colon cancers.

Is it surprising then, that toxic chemicals like formaldehyde and other organic solvents increase NMDA sensitization and stimulate glutamate release? Formaldehyde has already been classified as a human carcinogen by the US Environmental Protection Agency. Exposure to organic solvents also has been associated with a high risk of cancer.

If we follow this remarkable line of thought, it becomes evident that channel inhibitory agents like GABA, glycine, magnesium, and essential fatty acids, as well as glutamate-inhibiting herbs like Sophora flavescens, may have a role to play in combating cancer. Perhaps, as Ba speculates, “The most important targets to combat and prevent cancer are eliminating excitatory factors and creating favorable conditions for the body to restore the resting membrane potential.”  When normal cells are subjected to the constant stress of membrane hyper-excitability, we may have the preconditions for cancer. The stage may be set by chronic infections, ionizing radiation, toxic agents like solvents and pesticides, and dietary excitotoxins. In addition, nutritional deficiencies in inhibitory nutrients such as magnesium, glycine, and taurine, among others, add to the cellular load. The up-regulation of the cell membrane hyper-excitability triggers a cascade of adaptations that may lead to pathological changes. These might include cell dysplasia, fibrosis, cell death, or cellular proliferation.

In fact, according to a 2005 paper in the Journal of Membrane Biology, the last two decades have brought a remarkable increase of published evidence for the role of ion channels in tumor progression. The role of ion channels in both cell proliferation and cell death is extremely complex, say researchers at the University of Tubingen and the University of Salzburg: “Considerable further experimental effort is required to fully understand the complex interplay between ion channels, cell proliferation, and apoptosis.”

In sum, if we look beyond tissue inflammation to the cell membrane itself, we may discover that a new model of excitation and inhibition helps us create a powerful and elegant framework for chronic inflammatory conditions like asthma, and perhaps even cancer. In 2005, at the annual meeting of the American Association of Cancer Research, scientist Eyal Gottlieb claimed he had found a hallmark of cancer: bioenergetics. If the bioenergetics of the cell lies at the heart of malignant transformation, ion channel hyper-excitability may be a mechanism. It is with such frameworks and insights, that we begin the journey to truly effective therapeutic breakthroughs.

Back to top