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Department of Cell Biology, University of Cincinnati, Cincinnati, Ohio 45267
Address all correspondence and requests for reprints to: Nira Ben-Jonathan, Department of Cell Biology, University of Cincinnati, 3125 Eden Avenue, Cincinnati, Ohio 45267-0521. E-mail: Nira.Ben-Jonathan{at}uc.edu.
Lactotrophs are prolactin (PRL)-producing pituitary cells with several unique properties. Unlike most anterior pituitary cells, which are rather quiescent, the number of lactotrophs increases during estrus, pregnancy, and lactation. Whereas most pituitary cells are regulated by peptidergic hormones, the main regulator of the lactotrophs is dopamine, a neurotransmitter. Dopamine is the single most potent inhibitor of PRL production and lactotroph proliferation, and its actions are balanced by multiple stimulatory factors (1). In humans, abnormal proliferation of lactotrophs results in the formation of prolactinomas, the most common pituitary adenoma. Dopaminergic agonists such as bromocriptine and cabergoline have been highly successful in treating patients with prolactinomas (2, 3). In addition to suppressing serum PRL levels, these agonists reduce tumor mass by decreasing cell volume, reducing cell proliferation, and increasing apoptosis. About 15–20% of prolactinomas are resistant to dopamine, presumably due to loss of dopamine receptors or to faulty signaling pathways. For these patients, alternatives to dopaminergic treatment would be most valuable.
Although dopaminergic inhibition of lactotroph proliferation has long been recognized, the exact mechanism remained enigmatic for several reasons. First, it is more difficult to study inhibition than stimulation. Second, normal lactotrophs are highly heterogeneous with respect to membrane properties, receptor expression, and responsiveness to regulatory factors. Third, the most common lactotroph cell lines, e.g. GH3 cells, lack functional dopamine receptors (4). In this issue, Sarkar et al. (5) used complementary in vitro and in vivo approaches to provide compelling evidence that the growth-inhibitory action of dopamine is mediated, in part, by TGF-ß1.
It is important to incorporate this novel relationship between dopamine and TGF-ß in the context of the diverse actions of dopamine, which are best appreciated when examining temporal events. Within seconds, dopamine increases potassium conductance and inactivates voltage-sensitive calcium channels, resulting in membrane hyperpolarization, reduced intracellular calcium, and inhibition of PRL release (6). Within minutes, dopamine activates MAPK, suppresses adenylyl cyclase activity, and alters inositol phosphate metabolism, resulting in down-regulation of the PRL gene. Within days, dopamine inhibits lactotroph proliferation (1). It is unclear, however, whether all these events occur within the same cell or involve different lactotroph subpopulations and to what extent they proceed sequentially or in parallel.
The dopamine receptor family includes five members, with D1-like receptors (D1 and D5) classified by increased adenylyl cyclase activity in response to dopamine, whereas activation of D2-like receptors (D2, D3, and D4) results in its inhibition (7). Alternative splicing of the D2 receptor gene yields two isoforms, long (D2L) and short (D2S), which differ in 29 amino acids in the third intracytoplasmic domain. Although both isoforms have similar binding affinity to dopamine, they differ in coupling to G0/Gi proteins and to second messengers. D2L is predominant in the pituitary and its relative abundance, i.e. the utilization of a specific splice site, is regulated by sex steroids (8). In their study, Sarkar et al. (5) identified D2S as the mediator of growth inhibition by dopamine and showed that constitutive expression of D2S in PR1 lactotrophs that lack functional D2 receptors restored their responsiveness to growth inhibition by both bromocriptine and TGF-ß1. This is supported by the report that transgenic mice overexpressing D2S, but not D2L, have hypoplastic pituitaries and reduced PRL levels (9).
Lactotrophs receive input via endocrine, paracrine, juxtacrine, and autocrine interactions (Fig 1
). Endocrine agents originate from the hypothalamus, gonads, and the neurohypophysis and reach the lactotrophs via the blood. Paracrine factors are produced by cells of the intermediate and anterior lobes of the pituitary and reach their targets by diffusion. Juxtacrine interactions emanate from the extracellular matrix of adjacent cells. Autocrine agents are synthesized by the lactotrophs themselves. Hence, the overall secretory and proliferative activity of the lactotrophs reflects a balance between local and distant regulatory factors.
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, TGF-ß, and galanin, contribute to lactotroph homeostasis (10, 11). The role of TGF-ß is particularly intriguing, because TGF-ß1 and TGF-ß3, two isoforms encoded by different genes, stimulate and inhibit lactotroph proliferation, respectively (12). The TGF-ß superfamily includes TGF-ßs, activins, and bone morphogenic proteins. TGF-ß is synthesized as a precursor that must be activated by proteolytic processing. The mature protein initiates signaling by inducing heterooligomerization of two transmembrane receptors, TßRI and TßRII. Upon ligand binding, TßRII phosphorylates TßRI (13). Signaling is mediated by cytoplasmic Smad proteins, which translocate to the nucleus where they act as transcription factors. TGF-ß is a ubiquitous cytokine that inhibits epithelial cell proliferation. This is mediated by inhibitory Smads and involves repression of c-myc and up-regulation of cyclin-dependent kinase inhibitors, leading to G1 cell-cycle arrest (14). TGF-ß plays a dual role in tumorigenesis, as it inhibits growth of normal epithelial cells but accelerates the malignant process of late stages of tumorigenesis (15). It is uncertain whether such a switch also occurs in human prolactinomas that do not represent advanced malignancy. If prolactinomas that are resistant to dopaminergic intervention retain growth inhibitory responsiveness to TGF-ß1, this could provide novel therapy for these patients.
The involvement of estrogens in lactotroph physiology should not be overlooked. Estrogens provide positive input to the lactotrophs in a dopamine-dependent and dopamine-independent manner. Deletion of estrogen receptor (ER), but not ERß, results in marked suppression of PRL gene expression and reduced lactotroph density (16). Conversely, a dominant-negative ER mutant induces apoptosis in GH4 cells and suppresses tumor growth in nude mice (17). Upon removal of dopaminergic inhibition, as in D2 receptor-deficient mice, only females develop spontaneous prolactinomas (18). Recent studies also uncovered complex interactions between estrogen and TGF-ß ligands. Chronic exposure to estrogen of mice heterozygous for TßRII resulted in pituitary tumors (19), and estrogen treatment caused a reduction in TGF-ß1 and an increase in TGF-ß3 expression in lactotrophs (20, 21). Thus, the lactotrophs are subjected to a coordinated regulation by dopamine and estrogen, whose actions are mediated, at least in part, by alteration in the expression/release of specific TGF-ß isoforms.
In conclusion, these findings raise some yet-unresolved questions and open new avenues for research. For example, what intracellular pathways link the activation of either dopaminergic or estrogenic receptors and TGF-ß expression? Do such interactions involve other growth factors such as vasoactive intestinal peptide and fibroblast growth factor and/or nonlactotrophs such as folliculo-stelate cells? Is the strong mitogenic activity of estrogen, demonstrated convincingly in animal models and rodent lactotrophs, also applicable to human lactotrophs?
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Footnotes |
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Received July 18, 2005.
Accepted for publication July 21, 2005.
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References |
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in the anterior pituitary gland. Mol Endocrinol. 11:674–681
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