Molecular Basis Of Action

It is presumed that juvenile hormones exert their effects through receptor activation. However, it is a curious and surprising fact that, almost 70 years after its discovery by Wigglesworth, no definitive receptors have been identified. Even though no clear example of a JH receptor has been defined, a number of tantalizing possibilities have been suggested. One of these involves a nuclear receptor called ultraspiracle, or USP, a protein that is well known to regulate gene expression by forming a dimer complex with ecdysteroid receptors. The complex then binds to regulatory sequences on genes to turn them on or off. Grace Jones and Alan Sharp have demonstrated that JHs bind specifically to USP, although the affinity for this binding is lower than is generally expected for hormone-receptor interactions. It is proposed that JH binding to USP may influence how it interacts with ecdysteroid receptors (EcR) to regulate gene expression. The influence of JH and USP on EcR actions would seem to be a very plausible scenario for joint actions of JH and ecdysteroids, but further work is needed before USP is confirmed as a JH receptor.

Although early accounts of juvenile hormones focused on their uniqueness with respect to insect biology, the elusive-ness of JH receptors has prompted a closer look at possible similarities between signaling mechanisms common to insects and mammals. Indeed, the chemical structure of JHs resembles those of retinoids and farnesoids, both of which function in mammalian nuclear signaling by activating retinoic acid receptors, retinoid X receptors, and the farnesoid X receptor. JH and farnesoids are capable of activating some of these receptors, and some retinoids are known to have JH-like activity. It also has been observed that vertebrate thyroid hormones mimic some of the actions of JHs. Efforts are under way to identify receptors homologous to their mammalian counterparts as possible JH receptors.

Recently, workers taking a genetic approach to the problem identified a strain of fruit flies resistant to methoprene, an insecticidal juvenile hormone analog (see next section for details). The resistant flies have a defect in a gene that encodes MET, a protein related to the vertebrate aryl hydrocarbon receptor, which upon binding a diverse range of hydrocarbons activates a battery of genes involved in their metabolism. If the MET protein has similar properties, this might help explain why many synthetic chemicals such as fenoxycarb and pyriproxyfen have very potent JH-like effects, but bear little obvious structural similarity to natural JHs.

The failure after so many years to define a receptor for JH may indicate that, for this particular hormone, signaling does not conform to conventional modes of action. Perhaps JH binds to certain proteins, which then act as coeffectors or adaptor proteins to amplify or modify transduction of signals initiated by other hormones at conventional receptors. The obvious example is modification of ecdysteroid receptor action. It turns out that MET also is related to steroid receptor coactivators, which could bind to EcR and/or USP

to modify their effects on gene expression. Although little is known about the specific actions of MET at the present time, the MET resistance gene may hold the key to understanding the elusive molecular action of JHs.

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