Transmembrane Signaling

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5.3.1 Introduction

We have examined ways in which plant molecules effect the synthetic capacity of cells and their ability to proliferate or complete their life cycle. Another important way that exogenous molecules interact with cells and their functions is by various types of transmembrane signaling. Two types of signaling, ligand gated ion channels and G-protein/second messenger, are particularly relevant to the function of nerves and muscles. We will discuss these in detail and look at examples of how phytochemicals interact with them.

5.3.2 Ligand gated ion channels

Signaling of nerve cells and contraction of muscle cells are controlled in part by ion channels. Ion channels regulate the flow of sodium, potassium, and calcium across the cell membrane. Depending on the relative polarity on either

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FIGURE 5.7 Anticancer mechanisms.

a side of the membrane, the cell will either be resting, activated (depolarized), or in a recovering state (hyperpolarized) (Figure 5.8). Ion channel opening and

FIGURE 5.8 Cellular electrical events. Depending on the polarity on either side of the membrane, the cell will be in one of the four phases.

closing can be regulated by purely electrical forces as in the heart muscle. Cardiac cells depolarize and contract in unison via current flow at gap junctions along the membrane. Most ion channels, however, are opened or closed by the binding of chemicals, i.e., ligands. Binding causes conformational changes in the ion channel, allowing or inhibiting ion flow. As ions shift, the electrical potential across the membrane changes and the cell depolarizes. Depending on cell type, depolarization results in neurotransmission or muscle contraction. A hallmark of this kind of interaction is the extremely rapid reaction induced. Phytochemicals have historically played an important role in elucidating the nature of ligand gated ion channels. Nicotinic receptors at the neuromuscular junction on skeletal muscle are so named because the alkaloid nicotine causes depolarization of the muscle cells.

Plant-based medicines continue to have therapeutic value based on their ability to modify the actions of ion channels. In Ghana Desmodium adscendens is used to treat asthma. The symptoms of asthma can be modified by inhibiting the contraction of smooth muscles lining the airways. D. adscendens extracts can inhibit contractions in guinea pig intestinal smooth muscle. Three triterpe-noid glycosides (Figure 5.9) have recently been isolated from D. adscendens. These glycosides increase the probability that calcium-dependent potassium channels of bovine tracheal smooth muscle will be open.19 If potassium channels are open, the cell will hyperpolarize. It is then much more difficult to depolarize the cell and cause contraction. The traditional use of this herbal medicine in treating asthma is validated by understanding its mechanism of inhibiting smooth muscle contraction.

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FIGURE 5.9 Chemical structures of three triterpenoid glycosides from Desmodium adscendens from Ghana. These compounds modify the actions of ion channels.

FIGURE 5.9 Chemical structures of three triterpenoid glycosides from Desmodium adscendens from Ghana. These compounds modify the actions of ion channels.

5.3.3 G-Proteins and Second Messengers

Transmembrane signaling via G-proteins and second messengers is far more complicated than ligand gated ion channel signals and therefore has potential for many interactions with exogenous molecules. A G-protein sits within the membrane and is bound to guanosine diphosphate (GDP). In this mechanism, ligand binding to the receptor causes a change in the G-protein. GDP is phos-phorylated to GTP. This activates a cascade of enzymatic reactions which are the second messengers. Within this process there is amplification of the signal. There are two different series of second messenger reactions that can be stimulated. One is set in motion by formation of cyclic adenosine monophosphate (cAMP) which activates protein kinases. These enzymes in turn catalyze the phosphorylation of regulatory enzymes. Cells processes are turned on or off based on the phosphorylation state of the regulatory enzymes. The other second messenger reaction series begins with formation of inositol tri-phosphate which triggers release of intracellular stores of calcium ions. Calcium in conjunction with calmodulin activates or deactivates regulatory cellular enzymes. Protein kinase C is also activated and causes phosphorylation of other enzymes. No matter which second messenger pathway is activated, the net result is a change in the products or function of the effected cell based on the enzymes that are turned on or off. This produces the cellular response to the original message-bearing ligand.

Catacholamines, of which there are many analogs found in natural products, act on the sympathetic nervous system effector organs through two basic types of receptors, alpha and beta. The a-receptor reactions are mediated through the calcium/inositol system. P-receptors are connected to the cAMP pathway. The overall reaction of cells and organs to catacholamine stimulation will be based on the relative number and type of receptor on the individual cells.

Ma Huang (Ephedra sinica or E. equisetina) has been used for thousands of years in China. It is said to facilitate the circulation of lung Qi and control wheezing.20 It is also used to promote sweating and urination. Ephedra spp. are often found in cold and flu remedies, "energy" formulas, and weight loss formulas.21 These myriad effects might seem unreal until one realizes that all are related to stimulation of the sympathetic nervous system through a- and Preceptors. Pharmacological studies done at the turn of the century isolated ephedrine (Figure 5.10) and pseudoephedrine from the stems of E. sinica.22

FIGURE 5.10 Chemical structure of ephedrine from the stems of the plant, Ma Huang or Ephedra sinica. This drug acts to decongest the nose, relieving the symptoms of the common cold.

Ephedrine directly stimulates P-receptors to dilate bronchioles in the lung thus decreasing wheezing. Because of its lipid solubility, ephedrine crosses the blood-brain barrier and causes central nervous system stimulation and appetite suppression. Through indirect effects on other P-receptors, ephedrine and pseudoephe-drine increase heart rate and the force of heart contractions. This leads to increased blood flow to the kidneys and increased urine formation. Actions on a-receptors cause increased sweating and the constriction of blood vessels in the nasal mucosa. The later effect decongests the nose, relieving the symptoms of the common cold. Over-the-counter cold preparations often contain pseudoephedrine for this purpose. All these helpful effects have made Ephedra spp. popular ingre-

FIGURE 5.10 Chemical structure of ephedrine from the stems of the plant, Ma Huang or Ephedra sinica. This drug acts to decongest the nose, relieving the symptoms of the common cold.


Ephedrine d ents in modern herbal preparations. However, a plant with all these power! effects may also cause harm. Heart attacks, seizures, psychotic episodes, and deaths have been associated with the use of ephedrine containing herbal supplements. The FDA is currently considering regulation of these products.23 Persons with heart problems and high blood pressure should be especially careful when using these supplements.

5.3.4 Summary

Phytochemicals can have potent effects when they stimulate cells through the body's transmembrane signaling mechanisms. We have seen how Desmodium glycosides inhibit smooth-muscle contraction consistent with its traditional use in asthma. The ephedrine in Ma Huang has its multitude of actions mediated through G-proteins and second messengers. Another way phytochemicals can influence signal transmission is by increasing the signal itself, for example, increasing neurotransmitters (see essay on St. John's wort). There are many forms of cell-to-cell communication in the body. Phytochemicals have an important place in the modulation of that communication.

Essay on St. John's Wort: Increasing the signal

St. John's wort, Hypericum perforatum, has long been used in folk medicine. It is currently licensed in Germany for treatment of anxiety, depression, and sleep disorders. A recent meta-analysis of 23 randomized trials with data from 1757 outpatients shows that St. John's wort preparations are consistently superior to placebo for the relief of mild to moderately severe depression. The same study reports that when compared to standard pharmaceutical treatment, St. John's wort is as effective and appears to have fewer significant side effects.24

The exact mechanism of action of St. John's wort is unknown. There are several groups of compounds that may mediate its effects or act synergistically to produce enhanced mood. Lipid soluble hypericins (Figure 5.11) (0.06 to 0.75%), flavonoids (2 to 4%), xanthones (0.0004%), procyanidines (8%), hyperforin (2.8%), and ethereal oil (0.1 to 1%) are possible candidates because they can cross the blood-brain barrier. Of these, hypericins, xanthones, and hyperforin are characteristic of St. John's wort, while the other substances are ubiquitous in the plant kingdom.25 St. John's wort preparations are currently standardized by their hypericin content.

Early in vitro work showed hypericin to be an irreversible monoamine oxidase (MAO) inhibitor.26 Inhibition of this catabolic enzyme increases the amount of neuro-transmitters in the synapse between neurons and leads to enhanced mood. Recent studies in the same lab and others have questioned the viability of this mechanism in vivo.27 Another group has shown that the flavonoids and xanthones in Hypericum extracts inhibit catechol-o-methyltransferase, another enzyme that catabolizes neuro-transmitters.28 Still others have shown that Hypericum extract decreases the uptake of the neurotransmitter, serotonin, in rat synaptosomes.29 The same lab also showed decreased expression of serotonin receptors in a neuroblas-toma cell line after exposure to Hypericum.30 Decreased catabolism, decreased uptake, or decreased numbers of receptors all result in a relative increase in the amount of neurotransmitter signals the receiving cell experiences. St. John's wort

FIGURE 5.11 Chemical structure of hypericin, from St. John's wort, Hypericum perforatum. It is a drug used for the treatment of anxiety, depression, and sleep disorders.

FIGURE 5.11 Chemical structure of hypericin, from St. John's wort, Hypericum perforatum. It is a drug used for the treatment of anxiety, depression, and sleep disorders.

extract appears to have many potential mechanisms which may, in fact, be acting synergistically to increase the neurotransmitter signal.

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