Adaptive regulation of hormone interaction with receptor.

Exp. Clin. Endocrino!. Vol. 97, No. 1, 1991, pp. 13-28

J. A. Barth, Leipzig

Department of Sports Physiology (Head: Prof. Dr. bio!. sei. A. Viru), Tartu University, Tartu, Estonia/U.S.S.R.

Adaptive Regulation of Hormone Interaction with Receptor Vutu

With 10 Figures

Summary. Results of various studies suggest the existence of regulatory factors controlling the interaction of hormone with receptor and the postreceptor processes. Hence, the hormone effect is actualized through private and attending regulations. The first consists in the induction of specil ic effects of the hormone in target tissues. The attending regulation i realized as: 1) modulating regulation, acting on the state and number of cellular receptors, 2) metabolic regulation, acting via the other receptors on the cellular metabolism and changing in such a way the actualization of private regulation, 3) regulation of protein synthesis, acting on the synthesis of structure and enzyme proteins, participating in the actualization of private regulation. In physiologic meaning the modulating regulation consists in guaranteeing (to maintain the accordance between numbers of binding sites and acting signal molecules), homeostatic (to maintain the hormone balance through the alterations on the receptor level) and stress (to fascilitate the regulatory effects through changes on receptor or postreceptor levels) regulations.

Key word: Hormone receptor

The actualization of the hormone regulation depends on many factors. One of the most important factors is the hormone inflow to tissues. Alterations of the hormone concentration in the blood plasma are the main determinants of the hormone inflow into the tissues. However, these alterations have importance mainly in regard of free unbound fraction of hormone. Therefore the significance of the total hormone concentration depends on their relationships to the binding capacity of plasma proteins and to the intensity of the dissociations of protein-bound hormone complexes. The quantity of hormone arriving at the tissues is divided among various fractions (Fig. 1). One part of the arrived hormone content is bound by the sites connecting the hormone with enzymes catalyzing its metabolic degradation. This represents a loss of the hormone. Besides metabolic degradation, there are also biotransformations of hormones from more active forms into less active or inactive ones, or vice versa. Another part of hormone is bound with other proteins. This part of hormone is divided into the hormone content bound by specific cellular receptor and into hormone content bound unspecifically. There is also a fraction of free hormone. A dynamic equilibrium and cer-

tain exchange between these fractions have to be taken into the consideration. The amount of the hormone bound specifically by corresponding cellular receptors deter-

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mines the hormone effect. A respectable number of studies suggests that there exist at least three general factors, influencing the hormone effect. They are: 1) the state of hormone receptors, 2) the hormone interrelationship with other humoral regulators, 3) the substrate-enzyme ratio. The aim of this theoretical analysis is to evaluate the regulation at the level of hormone receptors in physiological considerations. Taking into account the.possibility of regulation of the effect of hormone specifically bound with its receptor, we have to consider that the hormonal regulation is actualized through (Fig. 2): 1) private regulation, 2) attending regulation. The private regulation consists in the induction of specific effects of the hormone in target tissues. These hormone actions are actualized through the interplay of hormone and its own receptors on the cellular membrane or in cytoplasm. The attending regulation is realized in the following forms (Fig. 2): modulating regulation, influencing the state and number of cellular receptors, metabolic regulation, acting through the other receptor on the cellular metabolism and facilitating or inhibiting in such a way the actualization of private regulation (e.g. through alterations of the substrate-enzyme ratios by changing the inflow of substrates and cofactôrs or outlow of products, through the energy attaining of the actualization of hormone effects, through the changes of electrolyte balance etc.), protein-synthetic regulation, acting through specific cellular receptors on the synthesis of structure and enzyme proteins, participating in the actualization of the private regulation.


dation or inacti-

15

A. VIRU, Regulation of Hormone/Receptor Interaction HORMONES

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Scheme of target points of the modulating regulation Fig. 4 Scheme of permissive action of cortisol Fig. 3

The particular case that combines the modulating regulation and adaptive regulation of protein synthesis is the control of the synthesis of receptor proteins. The experiments with administration of the cyclohexamide confirm that in lymphoma cells the protein synthesis is necessary to increase the number of glucocorticoid binding sites (Gruol and Bourgeois, 1987). The target points of the modulating regulation are the affinity of receptors to hormone, the number of receptors (binding sites) and the postreceptory processes (Fig. 3). There is a sufficient amount of data proving the existence of alterations on all of the

three levels of modulating regulation. In case of membrane receptors an important place belongs to the control of formation of the secondary messenger and of the chain


p tor SPECIFIC

16

Exp. Olin. Endocrinol. 97(1991) 1

of the processes actualizing the action of secondary messenger. In regard of the latter the typic of example is the permissive action of glucocorticoids (Ingle, 1952; Davies and Lefkowitz, 1984) on the efficiency of the sympatho-adrenal influences (Fig. 4). There are no direct evidences that steroid hormones intensify the transcription of receptor genes for additional synthesis of adrenoreceptors (Davies and Lefkowitz, 1984). The permissive action of glucocorticoids is considered to be connected with their action of the postreceptory processes (Exton et al., 1972; Granner, 1979). It has been suggested that the permissive action of glucocorticoids is founded on the regulation of the flux of calcium ions, that are necessary for cAMP formation and for the realization of its influence (Exton et al., 1972; Granner, 1979). The suggestion that the glucocorticoid permissive action is connected with the inhibition of cAMP-phosphodiesterase (Senft et al., 1968), is less evidented. Some results point at the possibility of the modification of hormone binding with adrenorecptors under the influence of steroid hormones (Davies and Lefkowitz, 1984). Nevertheless, it cannot explain the permissive action of Beside the secondary intracellular messenger, the formation of a tertiary one has been suggested to be among postreceptory processes (Hue and Rider, 1987). In a number of cases the interaction calcium - calmodulin is an important event (Oldham, 1982; Brown et al., 1985). In cases of cytoplasmic receptors the main steps of hormone interplay with receptor are the binding of hormone with receptor protein, the activation of steroid-receptor

complex and energetic attending of this process, the elimination of the inhibitor of translocation, translocation of steroid-receptor complex into nuclei and the binding of the complex on the DNA (Fig. 5), as well as the release of the steroid-receptor complex from the DNA, dissociation of the complex and deactivation of the receptor (Rous-

seau and Baxter, 1979; Schmidt and Litwack, 1982). In the first two steps receptor phosphorylation seems to be an important event (Moudgil, 1985; Rogozkin, 1985). A number of these steps may be the target of the modulating regulation. E.g. data are published indicating the regulation of binding of the receptor-glucocorticoid complex on the DNA (Picard et al., 1988). The increasing body of results of corresponding studies indicate various actions of hormones on its own receptor as well as on the receptors of other hormones. In most cases regarding the influence of homologous hormone on the receptor number a downregulation effect was observed: an administration of hormone induces a reduction of the number of its own receptors (Catt et al., 1979; Jänne and Kontula, 1980). Many

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glucocorticoids.

17

peptide hormone receptors, including those for somatotropin (Lesniak and Roth, 1976), insulin (Kahn et al., 1973; Bar et al., 1976), glucagon (Strikant et al., 1977), lutropin (Hsueh et al., 1976), thyreotropin (Rapport and Adams, 1976), thyreoliberin (Hinkle and Tashjian, 1975), vasopressin (Roy et al., 1976), corticotropin (Hornsby and Gill, 1977), and calcitonin (Wright et al., 1977) exhibit down-regulation by their homologous hormones. The same is demonstrated with regard to catecholamines (Mukherjee et al., 1975; Strittmaier et al., 1977), triiodothyronine (Samuels et al., 1976; LemarchandBérand et al., 1977), progesterone (Leavitt et al., 1977; Jänne et al., 1978) and prostaglandins (Lefkowitz et al., 1977). The glucocorticoid administration decreased the number of glucocorticoid binding sites in liver (Argutinskaya et al., 1981) and brain structures (Sarrieau 1986), the adrenalectomy increased it in liver (Rous et al., 1975), skeletal muscles (Mayer and Rosen, 1978) and brain structures (MeEwen, 1976; Sarrieau, 1986). After adrenalectomy the first peak of glucocorticoid binding in vivo and in vitro by various brain cells was noticed during the first 12 h. It was connected with the release of receptors from the complex with endogeneous hormone. After 1-5 days a new peak of glucocorticoid binding was observed. Now it was due to the synthesis of new receptor protein molecules (McEwen, 1979). In experimental diabetes the decreased level of circulating insulin accompanied with an increased number of specific binding sites of insulin in the target tissues (Thompson et al., 1987). It is suggested that the most plausible mechanism for receptor down-regulation is through internalization of the hormone-receptor complex (Catt et al., 1979). The downregulation constitutes, obviously, a physiological buffer mehanism within the target cell against changes in circulating hormone concentrations (Janne and Kontula, 1980). Controversely to these facts, in a number of cases hormone administration induced increased receptor concentration of the same hormone. Such a kind of "up-regulation" (Jänne and Kontula, 1980) was noted in regard of homologous hormone effects ou triiodothyronine (Tata, 1975), follitropin (Nimrod et al., 1976), prolactin (Posner et al., 1975) and angiotensin II (Aguilera et al., 1978) receptors. Exogeneous administration of physiological doses of estradiol initially depletes the cytoplasmic estrogen receptor content with a parallel accumulation of hormone-receptor complexes in nucleus (Zava et al., 1976). Since 8 h after estrogen administration an increase in cytosol receptor number followed it seemed to be dependent on protein synthesis (Mester and Baulieu, 1975).

The "down-regulation" effects were usually observed in cases of chronic administration of comparatively high hormone doses. Accordingly the increase of receptor number was observed in chronic hormone deficiencies. On the other hand, the "up-regula-

tion" effects are connected with more physiological conditions. It is reported that in accordance to the level of estradiol in blood the number of its receptors increases in uterus during the first days of pregnancy (Baulieu, 1975). In rats 20 h after muscular activity of maximal possible duration a low glucocorticoid level was observed in blood as well as a decreased number of dexamethasone-binding sites in cytoplasm of myocardiocytes and in oxidative fibers of skeletal muscles (Korge et al., 1981). Increase of the corticosterone concentration in blood plasma in result of daily exercises was associated with augmented number of specific binding sites for glucocorticoids per 1 mg of protein (Eller et al., 1981). After corticosterone administration to rats during 1-4 days, suppressing corticoliberine secretion, the number of corticoliberine receptors decreased in adenohypophysis parallel to the drop in corticotropin secretion (Hauger et al., 1987). Hypoinsulinemia due to a lipid-rich feeding decreased the number of insulin receptors in adipocytes (Hissin et al., 1982). These facts suggest that the modulating regulation exists in various forms in meaning

of its physiological significance. The data about the "up-regulation" effects indicate


A. VIBU, Regulation of Hormone/Receptor Interaction

18


that one of these forms is a guaranteeing regulation, the aim of that is to maintain the accordance of the number of binding sites to the number of the acting regulatory molecules (Fig. 6). The facts of "down-regulation" effects lead to the suggestion, that there exists also a homeostatic form of modulating regulation (Fig. 6). The aim of such alterations in receptor proteins consists in maintaining the regulatory actions close to the normal level despite the prolonged changes of hormone concentration in blood.

GUARANTEEING REGULATION

INCREASED NO OF RECEPTOR

HOMED STATIC

REGULATION

DECREASED NO OF R EC E PTO R

CHRONICALLY REDUCED

HORMONE LEVEL

Fig. G Scheme of guaranteeing the homeostatic regulation on the hormone receptor level

Protein-rich feeding induced a pronounced increase of androgen receptors in skeletal muscles (Snochowski et al., 1986). Muscle atrophy after tendotomy or denervation was associated with an increase in the concentration of androgen and glucocorticoid receptors, expressed per mg of cytoplasma protein or per g of muscle wet weight (Saartok, 1983). Obviously,'the guaranteeing form of modulating regulation may dependent be-

side the hormone level also on the actual need of hormonal action on the metabolic processes.

During a prolonged incubation of cellular culture of adenohypophysis with thyreoliberine, the number of thyreoliberine binding sites decreased to 113 of normal (Tata, 1975). A high corticosterone level due to its administration decreased the number of pituitary c.orticoliberine receptor (Hauger et al., 1987). A marked increase in plasma corticoliberine concentration that occurred after adrenalectomy was associated with a progressive decrease of pituitary corticoliberine receptors (Aguilera et al., 1982; Wynn et al., 1985). Most of this decrease was due to receptor down-regulation. It was accompanied by comparable decrease in maximal corticoliberine-stimulated adenylate cyclase activity and sensitivity to corticoliberine. Such decreases in corticoliberine receptors and adenylate cyclase activity in adrenalectomized rats were prevented by dexamethasone treatment suppressing corticoliberine production (Wynn et al., 1985). Analogous is the effect of gonadectomy on pituitary gonadoliberine receptors in the female mouse: a decrease of binding sites occurs after castration (Naik et al., 1984). Evidently, there exists a variant of homeostatic regulation, that consists in a decrease of the receptor number, participating in stimulation of the hormone production, to avoid the prolonged activation of the system.


CHRONICALLY ELEVATED HORMONE LEVEL

A. Vuw, Regulation of Hormone/Receptor Interaction

19

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Variants of homeostatic regulation on the hormone receptor level

Into the group of homeostatic regulation on the receptor level belongs also the increase of the receptor number in nervous structures, actualizing the negative feed back during the activation of the system (Fig. 7). For example, the administration of triiodothyronine increased the number of its receptors in pituitary cells but not in liver cells (Tata, 1975). In pituitary cells triiodothyroriine receptors actualize the feedback inhibition of thyreotropin secretion, in liver - the metabolic effect of triiodothyronine. In stress situation another picture reveals, suggesting that there exists a stress regulation at the receptor level that is opposite to the homeostatic regulation. In stress the specific binding of corticosterone did not change in hypothalamus that stimulates the activity of pituitary-adrenocortical system, but decreased in hippocampus (Patacchioli et al., 1984; ukov, 1987). Evidently, the stress regulation at the receptor level avoids suppression of the system via negative feed back action with the aid of diminution of the number of receptors in related nervous structures (Fig. 8) The accomplishment of these regulatory changes with the guaranteeing regulation is not excluded: a simultaneous increase of the number of receptors in structures, actualizing the activation of the system for maintaining the correspondence of the number of binding sites to the amount of regulatory molecules. For example, the immobilization stress induced an increased number of opioid and dopamine receptors in rat striatum (Zeman et al., 1988). In the same situation an increased affinity of muscarinic cholinergic receptors was noticed in hippocampus, septum and pons without changes in the receptor number. In striatum the receptor number increased and dissociation constant decreased (Takayama et al., 1987). Jncreased STRESS

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NO IN NERVOUS STRUCTURES OF NEGATIVE FEED BACK

20


In cases of prolonged stress situations opposite results were obtained. In daily immobilization of rats for 2.5 h the number of ß-adrenoreceptors decreased in heart, hypothalamus and brain (Torda et al., 1985). In accordance, a decreased sensitivity of and ß1-adrenoreceptors was observed in rats during prolonged cold stress (Plotnikov

ture, the functional and metabolic effects of catecholamines, vasopressin, insulin and triiodothyronine altered in humans (Medvédev and Kosenkov, 1989). After stress the hypersecretion of corticosterone switches out in dependence on the state of glucocorticoid receptors iii cells of hippocampus (Sapolsky et al., 1984). During 2-4 h after 20 mm immobilization approximately 50% of glucocorticoid receptors occurred in complex with hormone and bound on the chromatine of nuclei of hippocampal neurons (Meaney et al., 1988). On the second day after an immobilization stress the number of corticoliberine receptors was decreased (Hauger et al., 1988). In regard of all variants of the modulating regulation at the receptor level a question remains: what are the regulating agents and how do they act. In 1975-1976 it was affirmed that the regulation of the concentration of hormone receptors by the same hormone is a common phenomenon, observed in regard of steroid and peptide hormones, catecholamines and growth factors (Baulieu, 1975; DeMetyts et al., 1976): Nevertheless, it is not certain whether all of the above mentioned changes were actualized by "own"

hormones or did the other regulatory factors participate as well? These questions are still waiting their answers. The obtained data point at the possibility of the cooperation of various regulators in accomplishment of the modulating regulation. It is established that the number of glucocorticoid receptors decreases in hippocampus as a result of stress regulation through the action of serotoninergic structures (Angelucci et al., 1982). The administration of an antiserotoninergic drug completely inhibited the calcitonin-induced increase of ß-endorphin, corticotropin and cortisol secretion (Laurian et al., 1988). At least in the cells of lymphoma the ability to bind the glucocorticoids depends on the cAMP-depending proteinkinase (Gruol and Bourgeois, 1987). The thyroid hormones fasdiitate the ontogenic development of the glucocorticoid receptors in lungs and hippocampus (Morishige, 1982; Meaney et al., 1987), but not in hypothalanius and pituitary (Meaney et al., 1987). It was also demonstrated that the hypothyroidism modulates the glucocorticoid receptors (Leseney et al., 1987 Meyney et al., 1987). Thyroid hormones regulate also ß-adrenergic receptor sites (Williams et al., 1977). The glucocorticoids are not a single hormone, possessing the permissive action. In some cases they themselves require the permissive action of other hormones. The preliminary administration of thyroid hormones to culture of pituitary cells is necessary for induction of the somatotropin synthesis by glucocorticoids. In isolated hepatocytes cAMP or glucagon occurred to be necessary for induction of tyrosine-aminotransferase by glucocorticoids (Harris and Baxter, 1979). On the other hand, cortisol is capable to increase the binding of insulin as well as the production of insulin-receptor mRNA in the culture of human lymphocytes (Shibashani et al., 1988). Glucocorticoids modulate the phosphorylation of insulin, epidermal growth factor receptors, and kinase activity in liver (Karasik and Kahn, 1988). Glucocorticoids act also on the serotoninergic and noradrenergic systems of brain. This action is realized on the mediator-receptor interaction and secondary messenger levels (McEwen, 1987). Adrenalectomy induced a decrease in number of somatostatin receptors in rat brain (Rodriguez et al., 1988). A widespread discovery of corticoliberine (Smith et al., 1986) and its receptors (Aguilera et al., 1986; De Souza, 1987) in brain leads to a consideration of it as a neuro-


et al., 1987). Reasonably, in prolonged stress the stress regulation changes by the homeostatic form of modulating regulation to avoid the harmful consequences of prolonged stress. The expression of the change is a decreased number of stress hormone receptors. In accordance, during prolonged action of both high or low environmental tempera-

A. Vxnu, Regulation of Hormone/Receptor Interaction

21

modulator. It has been demonstrated that the corticoliberine blocks the Ca-depended conductance in nervous cells (Aldenhoff, 1986). A multiple role of calcium ions in various cellular processes, including the action of many hormones, allows to suggest the possibility of the modulatory regulation by corticoliberine through the alterations in calcium shifts. Beside corticoliberine, the modulating properties are common for many other neuropeptides. ß-Endorphin inhibits some effects of calmodulin (Clouet et al., 1983). It may be a possibility of actualizing the modulatory effects of enclorphins The opioid receptors participate in the mechanism of corticotropin release (Pfeiffer et al., 1985). The blockade of opioid receptors enhanced the corticotropin secretion under the influence of corticoliberine (Ehrenreich et al., 1987) and intensifies the rise of epinephrine and norepinephrine concentrations during muscular work (Grossman and Bouloux, 1984) and after administration of acetyicholine directly into the gland (Dietrich et al.,

et al., 1985).

In rats estrogens increase the concentration of pituitary thyreoliberine .receptors, thyroid hormones counteracts to this effect (Delean et al., 1977). Estrogens inducp also a marked increase in the number of ovarian lutropin binding sites (Lee and Ryan, 1974)

as well as in the affinity and number of binding sites of uterine oxytocin receptors (Soloff, 1975). Estrogens promote also the synthesis of cytoplasmic receptors of progesterone (Jänne et al., 1978; Leavitt et al., 1977), androgens (Moore et al., 1979) and glucocorticoids (Mayer and Rosen, 1978). Androgens counteract to the estrogen effect. on glucocorticoid receptor (Mayer and Rosen, 1978). Muscle hypertrophy occurred to be associated with elevated concentration of glucocorticoid receptors. This effect. was independent on androgen action (Tanaka et al., 1988). Diabetes led to a deficiency of glucocorticoid receptors (Mayer and Rosen, 1978). Progesterone administration brings about a decrease in the cytoplasmic and nuclear estrogen receptors of endometrium and myometrium in both animal models and in man (Tseng and Gurpide, 1975; Jänne et al., 1979; ilsuch et al., 1975, 1977). Conclusions

The functional endocrine systems contain not only the alterations in production of related hormones for private regulation, but also a complicated cooperation of regulatory actions in the course of the attending (modulating, metabolic and adaptive protein synthesis) regulation. The modulating regulation may be addressed to the changes in affinity of the cellular receptors to hormone, to the number of receptors and to the postreceptory processes. The modulating regulation may be in form of guaranteeing homeostatic and stress regulations. The existence of the regulation of hormonal signal on the two levels - on the level of cells, producing the signal molecules, and on the level of receptors, receiving them - makes a variability in the tactics of adaptive alterations possible. For example, individual analysis of changes of various hormones. and endorphine during prolonged exercises revealed various variants of dynamics, including even differences in direction of responses (Fig. 9, 10). In a number of cases the increase of corticotropin concentration did not coincide with the elevation of cortisol level in blood suggesting a blockade at the level of corticotropin receptors in adrenals. (Viru et al., 1989). A variability of hormonal changes during different influences seems to be completely natural and does not necessarily contain an information, possessing the evaluation of the quality of adaptation.


1988). On the other hand, the somatostatin excludes the inhibiting action of f3-endorphin

on the catecholamine production by adrenals (Golovanov, 1980). A factor that acts on the opioid receptors in brain is androgens. After castration their affinity to endorphins dropped, but after the testosterone administration it was restored again (Maggi

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Fig. 10 Four variants of dynamics of ß-endorphin (pM/i) in healthy persons during 2-hour exercise on bicycle ergometer (each variant is indicated by two individual cases)

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Author's address: Dr. ATKO VIRIl, 18 Ylikooli, Tartu 202400, Estonia, USSR


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Functional Regulation of Dopamine D₃ Receptor through Interaction with PICK1.

[Regulation of hormone receptor (author's transl)].

Regulation of luteinizing hormone-releasing hormone receptor binding by heterologous and autologous receptor-stimulated tyrosine phosphorylation.

Sense-antisense complementarity of hormone-receptor interaction sites.

Regulation of adrenal atrial natriuretic hormone receptor subtypes.

Epigenetic regulation of thyroid hormone receptor beta in renal cancer.

Thyroid hormone receptor mutations that interfere with transcriptional activation also interfere with receptor interaction with a nuclear protein.

CG receptor.

The growth hormone secretagogue receptor: its intracellular signaling and regulation.

Negative and positive transcriptional regulation by thyroid hormone receptor isoforms.

Differential regulation of thyroid hormone receptor messenger ribonucleic acid levels by thyrotropin-releasing hormone.

The biology of GM-CSF: regulation of production and interaction with its receptor.

Novel pathway for thyroid hormone receptor action through interaction with jun and fos oncogene activities.

Dominant negative transcriptional regulation by a mutant thyroid hormone receptor-beta in a family with generalized resistance to thyroid hormone.

Ovarian follicular development in the rat: hormone receptor regulation by estradiol, follicle stimulating hormone and luteinizing hormone.

Interaction of JAK with steroid receptor function.

Posttranscriptional regulation of oral bacterial adaptive responses.

Innate lymphoid cell regulation of adaptive immunity.

Interaction of human growth hormone with isolated rat liver cells.

Overexpression of thyroid hormone receptor β1 altered thyroid hormone-mediated regulation of herpes simplex virus-1 replication in differentiated cells.

GHF-1) and potential interaction with a thyroid hormone-inhibitory element.

chorionic gonadotropin (CG) receptor and human CG for receptor-hormone interaction.

Interaction of early life stress and corticotropin-releasing hormone receptor gene: effects on working memory.

Effects of thyrotropin on the thyroid cell membrane: hyperpolarization induced by hormone-receptor interaction.