Control of lactotrop proliferation by dopamine: Essential role of signaling through D2 receptors and ERKs

Abstract

Dopamine is thought to exert a negative control on lactotrop cell proliferation and prolactin production. Indeed, mice lacking the D2 receptor develop pituitary tumors of lactotrop origin. Because lactotrops express two isoforms of D2R, D2L, and D2S, in a specific ratio, we decided to explore the physiological importance of their relative abundance in vivo. Thus, we generated transgenic animals overexpressing either D2L or D2S in lactotrops. Increased expression of D2S, but not of D2L, leads to mitogen-activated protein kinase (MAPK) induction, which results in pituitary hypoplasia. On the other hand, levels of phosphorylated MAPKs are drastically reduced in pituitary tumors generated by the absence of D2-dependent signaling. These results underline a critical role of D2-mediated MAPK activation in lactotrop proliferation. Furthermore, whereas D2S overexpression results to a drastic reduction of prolactin, D2L overexpression elevates it. Our findings underscore a different role of the two D2R isoforms in the pituitary gland physiology.DA ͉ D2L and D2S receptors ͉ pituitary ͉ MAPK A ctivation of dopamine D2 receptor (D2R) regulates several physiological functions in the central nervous system as well as in the pituitary gland (1-3). In the pituitary, the signal transduction activated by D2 receptors negatively regulates prolactin (PRL) synthesis and release (4, 5). Analyses of D2R null mice have illustrated a control on the proliferative rate of lactotrops by D2R. In the absence of D2R signaling pituitary tumors arise of lactotrop origin (prolactinomas) in 100% of aged females and only very rarely in males (2, 6, 7). In humans, prolactinomas might regress on treatment with dopaminergic agonists such as bromocriptine and are generally more common in women than in men (8, 9). Thus, similar D2R-mediated signaling seems to exist at the pituitary level in humans and mice. It is presently unclear through which pathway the activation of D2R is able to control lactotrop proliferation.D2Rs exist into two molecularly distinct isoforms, D2L and D2S. Both isoforms, generated by alternative splicing from the same gene, have similar pharmacological and biochemical profiles in vitro, despite the presence of an additional 29 amino acids in the D2L isoform (10-13). This additional segment is located in the third intracellular loop of the putative receptor structure, a region involved in the coupling to the G proteins. In vitro studies suggest that the two isoforms might activate different signaling pathways in vivo (14). Analyses with genetically modified mice have recently supported the hypothesis that D2L and D2S might have different functions in vivo (15,16).The two isoforms are produced in a well-defined D2L͞D2S ratio. The D2L isoform is always more abundant than D2S. This ratio is respected in the pituitary and in the brain with the exception of mesencephalic regions where it is inverted (13, 17). The physiological role of the ratio of the two different isoforms is still unknown. In this study, we have addressed this point b...

Genesis of Prolactinomas: Studies Using Estrogen-Treated Animals

“…There appears to be a close association between the use of oral estrogenic contraceptives and the onset of amenorrhea, often accompanied by galactorrhea [25][26][27]. Certain subsets of humans and animals are more sensitive to estrogen's mitogenic properties than the general population [28,29]. Hence, estrogen can be considered a risk factor for the development of prolactinomas in some laboratory animals and in a certain population of humans.…”

Structurally conserved C-RFa revealed prolactin releasing activity in vitro and gene expression changes in pituitary of seasonally acclimatized carp

“…This is in agreement with the observation of pituitary explants, which did not release PRL in the untreated culture (Flores et al 2007). Mainly lactotrophs were identifi ed by immunofl uorescence in the primary cell culture, suggesting that the missing inhibitory effect of hypothalamic dopamine led predominantly to proliferation of lactotrophs (Asa et al 1999;Iaccarino et al 2002).…”

Regulatory Roles of Heterogeneous Nuclear Ribonucleoprotein M and Nova-1 Protein in Alternative Splicing of Dopamine D2 Receptor Pre-mRNA

“…Among them, the dopamine D2 receptor (D2R) 4 is a major target of pharmacological interventions for the treatment of Parkinson disease, schizophrenia, depression, and pituitary tumors. The generation of D2R knock-out mice has highlighted its key role in the control of motor functions (2), regulation of reward circuitries (3,4), and pituitary physiology (5,6). D2R also acts as the main dopaminergic autoreceptor (7)(8)(9).…”

“…D2L differs from D2S by an additional 29 amino acids encoded by exon 6, inserted within the third cytoplasmic loop of the receptor, the region interacting with G proteins. This insertion likely accounts for a differential interaction of D2L and D2S with G proteins (11), activation of distinct downstream signaling pathways (6,12), and function (12,13). Indeed, analyses of D2L knock-out mice suggest that D2L is involved mainly in the control of postsynaptic functions, whereas D2S is involved in the control of dopamine neuron firing and dopamine release (8,13).…”