Beating the Odds with Big K

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Science  17 Sep 1999:
Vol. 285, Issue 5435, pp. 1859-1860
DOI: 10.1126/science.285.5435.1859

When it comes to longevity, women have an advantage over men because they are less susceptible to cardiovascular disease, at least until the onset of menopause (1). This advantage is due largely to the beneficial effects of their estrogen hormones on blood vessels (2). Estrogen crosses the plasma membrane of vascular endothelial and smooth muscle cells and binds to specific intracellular receptors. The ligand-receptor complex then alters gene expression, which results in protection of blood vessels from injury and atherosclerosis. In addition to these long-term protective effects, estrogen induces rapid dilation of blood vessels without altering gene expression. However, it is not clear whether estrogen mediates this effect by binding to novel receptors in the plasma membrane, or by activating intracellular nongenomic pathways. In a study on page 1929 of this issue, Valverde et al. (3) seek to resolve this conundrum. They report that a potassium ion (K+) channel known to participate in the rapid regulation of blood vessel tone is directly activated by 17β-estradiol, the major circulating estrogen in premenopausal women.

Contraction of vascular smooth muscle decreases the diameter of blood vessels, and thus controls blood flow and blood pressure. Graded changes in the voltage across the plasma membrane of smooth muscle cells in the blood vessel wall result in graded muscle contraction. When the intracellular potential becomes more positive (depolarization), voltage-dependent Ca2+ channels in the plasma membrane are activated. The entry of Ca2+ into smooth muscle cells through these channels then leads to muscle contraction. This process can be reversed by the opening of K+-selective channels. The increased efflux of K+ from muscle cells induces the membrane potential to become more negative, which closes the Ca2+ channels, resulting in muscle relaxation (4). The realization that modulating the activity of K+ channels can be used to control blood pressure has sparked considerable interest in identifying K+ channels in vascular smooth muscle cells and in developing drugs to modulate them (5).

One class of K+ channel that participates in the relaxation of smooth muscle is the large-conductance, calcium-activated K+ channel (4), also affectionately referred to as the Maxi K+ or Big K channel because of its unusually large conductance. Maxi K+ channels differ from most other K+ channels in that their activation is under dual control—switched on by either depolarization or by an increase in intracellular Ca2+ (6). This dual (often synergistic) activation is possible because of the Maxi K+ channel's structure. Each of the four α subunits that assemble to form a functional Maxi K+ channel (7) can be divided into two parts: a core (which is similar to that in other voltage-activated K+ channels) complete with a voltage sensor, and an extended tail that houses an intracellular Ca2+ binding domain (8). In addition to the pore-forming α subunits common to all Maxi K+ channels, those in vascular smooth muscle have an auxiliary β subunit that combines with α subunits in a one-to-one stoichiometry (see the figure) (9). The β subunit has profound effects on Maxi K+ channel activity, decreasing by 5- to 10-fold the concentration of intracellular Ca2+ required to keep the channel open 50% of the time compared with the β subunit-deficient Maxi K+ channels in skeletal muscle (9, 10). That the activation of Maxi K+ channels in vascular smooth muscle leads to rapid dilation of blood vessels raises the question of whether estrogen binding to the β subunit is involved in this process.

Maximizing the benefits of K+ channels.

The Maxi K+ channel of vascular smooth muscle cells is composed of both α and β subunits (top), whereas that of skeletal muscle cells is composed of α subunits alone (bottom). 17β-Estradiol binds to and increases the activity of Maxi K+ channels with β subunits. The resulting efflux of K+ from the vascular smooth muscle cells results in closure of Ca2+ channels and relaxation of the muscle in the blood vessel wall.

Valverde et al. (3) address this question by expressing human Maxi K+ channels in Xenopus oocytes and examining the effects of estrogen on channel activity. They found that 17β-estradiol increased the activity of Maxi K+ channels composed of both α and β subunits, but had no effect on channels composed of α subunits alone. When estrogen was coupled to bovine serum albumin (which prevents the hormone from crossing the plasma membrane), the Maxi K+ α/β channel was still activated, demonstrating that estrogen acts extracellularly. Estradiol can still activate Maxi K+ channels reconstituted into artificial membranes (provided both α and β subunits are present), indicating that no intracellular signaling is required and that the Maxi K+ channel is a receptor for estrogen. To corroborate this deduction, Valverde and colleagues performed binding studies. Oocytes expressing Maxi K+ channels composed of α and β subunits, but not of α subunits alone, bound greater amounts of 3H-estradiol. Human embryonic kidney cells expressing the α/b channels show greater fluorescence after exposure to estradiol tagged with a fluorescent label compared with cells expressing channels containing only the α subunit. These experiments indicate that the direct binding of estradiol to an external site on Maxi K+ channels—which is available only when the β subunit is present—increases channel activity.

New methods for treating cardiovascular disease are continually being sought. There is accumulating evidence that postmenopausal estrogen-replacement therapy decreases the risk of major coronary heart disease (1). However, the benefit of estrogen treatment decreases with long-term hormone use because of the increased risk of breast cancer (11). Consequently, tissue-specific, estrogen-like drugs that preserve the beneficial effects of estrogen on the cardiovascular system without having deleterious effects on other organs are needed. The finding by Valverde et al. that estrogen directly activates vascular smooth muscle cell Maxi K+ channels may pave the way for the rational design of new drugs for the prevention of cardiovascular disease.


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