For nearly fifty years until the 1980s, most explanations for the mechanism of action of thyroid hormone were based on a direct interaction of the hormone with individual enzymes, membrane, and other cellular preparations with ligand-binding properties, that is, nongenomic mechanisms ([2
]; see ). But the mid-1980s saw a sea change in our thinking about the mechanism of action, not only of TH, but also of all steroid hormones, retinoic acid, and many nonsteroidal signalling molecules, with the discovery of nuclear receptors, that is, signals acting via genomic mechanisms [7
]. The powerful tools of gene cloning and sequencing and cell transfection have helped place these later genomic studies on a firmer biochemical base. More recently, however, several investigators have reinvoked the possibility that TH as well as steroid hormones and other signalling molecules acting via nuclear receptors also exert nongenomic actions through extranuclear sites. The latter is particularly relevant to those that involve rapid responses to the same signal acting relatively slowly via genomic mechanisms (see, e.g., [40
]). This, in turn, raises the wider question for all hormonal and nonhormonal signals as to whether they operate through the same receptor, perhaps located in different cellular compartments, or whether the different genomic and nongenomic responses are the outcome of interactions with different receptors, irrespective of their locations. While, unlike nuclear receptors, we still await the isolation and precise information on the structure of “nongenomic” receptors, it is of some interest to consider some of the possible situations arising out of whether the multiplicity of responses to a given hormone arise from its interaction with a unique or multiple receptors, as considered below.
As already shown in , thyroid hormone exerts a wide range of actions in different tissues and organs (e.g., control of metamorphosis in amphibians and basal metabolic rate in mammals). The same is true of signalling molecules. Furthermore, almost all membrane and nuclear hormone receptors are highly conserved as cellular homologues of the oncogenes c-erb
B and c-erb
A, respectively, which explains why several hormones can functionally interact with their receptors in a wide range of phyla. For example, analogous domains of the receptors of insect hormone ecdysone and the vertebrate thyroid hormone can be swapped to activate transcription in insect and mammalian cells in a reciprocal fashion (see [44
]). One is thus faced with the question as to how, if both the hormonal signal and its receptor are conserved through evolution, their physiological actions are not. It underlines the importance of an understanding of the postreceptor “Black Box” in order to move further down the pathway in the search for the mechanism of multiple actions of a given hormone.
To further consider the fact that hormone receptors are evolutionarily conserved, but that their downstream responses are not, three hypothetical, oversimplified, models are presented in . First, If one accepts that there is a unique receptor for thyroid hormone in a given cell (model 1), is it possible at some point along the chain of postreceptor downstream responses that there is a point where chains of events diverge, such that it could explain the multiplicity of the physiological actions of the hormone, as shown in ? This possibility of divergence has led some investigators to look for drugs to selectively enhance or block some TH actions of, as has been implicit in the blocking of cardiac effects, but not cholesterol-lowering effects of, thyroid hormone derivatives [45
]. Another possibility for the multiplicity of responses is that the receptor is the same but that it is present in different cellular locations. For example, it has been suggested by some that the nuclear thyroid and steroid hormone receptors are also located in the plasma membrane and mitochondria which could give rise to different actions with different latency periods [40
]. Recently, Cheng et al. [46
] have claimed that the different responses to TH are initiated not only in the nucleus, but also in the plasma membrane, cytoplasm, and mitochondria (model 2). But firm evidence that these different locations represent distinct functional receptor entities such that each would be responsible for a distinct response to the hormone is however lacking.
Figure 3 Three hypothetical models for thyroid hormone action depicting permutations of multiple hormonal interplay at the postreceptor level, represented by “Black Boxes” A, B, and C. According to model 1, the simplest situation is that T3 interacting (more ...)
The establishment of two distinct receptors for thyroid hormone, TRα
, has allowed the separation of different actions of TH at the receptor level. It has also meant that a well-characterized human thyroid disorder (thyroid hormone resistance) could be explained on the basis of a mutation in one and not the other TR isoform ([43
]; see Refetoff, this issue). For some other hormones or cellular signals, it is also possible to explain different responses to the same hormone on the basis of interactions with distinct receptors. For example, the actions of oestrogen via ERα
(oestrogen receptors α
) explain the multiplicity of their biological actions as resulting from an initial interaction with distinct receptors in different cell types. This possibility is confirmed by the identification of oestrogen receptors α
present in the different cell types but in the same intracellular location, that is, the nucleus [48
Another possible model suggests that the multiplicity of action is a reflection of separate postreceptor downstream chains of responses (model 3), but, again, no convincing experimental evidence has been provided. One can invoke other models, such as a modification of that shown in model 3, whereby the action of one hormone acting through one receptor is qualitatively or quantitatively modulated by the downstream action via responses to another receptor (known or unknown) located in a different part of the target cell. The downstream modifications of responses could be compared to how Brivanlou and Darnell [49
] conceptualize signals generated from the cell membrane can modify the chain of responses to a signal generated from within the cell, such as from the cell nucleus. The second (or third) signal involved in cross-regulation need not be hormonal in all cases and can be a growth factor, vitamin, antibody, and so forth. Scanning the literature on hormone action in general, many examples can be found whereby one or more hormones can modify the action of another, irrespective of whether or not these hormones act through nuclear or membrane receptors. This is depicted in model 3 of in which hormones H2
modify the response to T3
, each acting through its own receptor. Some examples of hormonal cross-regulation can be found in a most recent review [50
In all three models depicted in , the crucial element is the Black Box. Whereas there has been considerable progress, especially since the molecular cloning of hormonal and nonhormonal receptors, in understanding the fine details of receptor structure, function, and their intermolecular complexes, it has not yet been possible so far to link these data to the final physiological action of a given hormone. It is this gap in our knowledge of receptor function and its relevance to the final physiological action of the hormone (in this case thyroid hormone) that is represented by the Black Boxes in . The Black Box could be a one-step or multistep event, the latter most likely if recent ideas of convergence of signals, networking, or proteomics turn out to be the crucial elements for furthering our understanding of mechanisms of hormone action. It represents a major challenge currently to fully understanding the mechanism of hormone action, in contrast to an enormous cataloguing of the effects produced by hormones in order to explain the multiplicity of hormone action. An understanding of the immediate postreceptor response by the target cell to the hormonal signal is essential to enhance our understanding of how hormonal signals accomplish their physiological actions.