Dysfunctions of dopaminergic homeostasis leading to either low or high dopamine (DA) levels are causally linked to Parkinson's disease, schizophrenia, and addiction. Major sites of DA synthesis are the mesencephalic neurons originating in the substantia nigra and ventral tegmental area; these structures send major projections to the dorsal striatum (DSt) and nucleus accumbens (NAcc), respectively. DA finely tunes its own synthesis and release by activating DA D2 receptors (D2R). To date, this critical D2R-dependent function was thought to be solely due to activation of D2Rs on dopaminergic neurons (D2 autoreceptors); instead, using site-specific D2R knock-out mice, we uncover that D2 heteroreceptors located on non-DAergic medium spiny neurons participate in the control of DA levels. This D2 heteroreceptor-mediated mechanism is more efficient in the DSt than in NAcc, indicating that D2R signaling differentially regulates mesolimbic-versus nigrostriatal-mediated functions. This study reveals previously unappreciated control of DA signaling, shedding new light on region-specific regulation of DA-mediated effects.

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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...

The leucine-rich repeat kinase 2 (LRRK2) gene was found to play a role in the pathogenesis of both familial and sporadic Parkinson’s disease (PD). LRRK2 encodes a large multi-domain protein that is expressed in different tissues. To date, the physiological and pathological functions of LRRK2 are not clearly defined. In this study we have explored the role of LRRK2 in controlling vesicle trafficking in different cellular or animal models and using various readouts. In neuronal cells, the presence of LRRK2G2019S pathological mutant determines increased extracellular dopamine levels either under basal conditions or upon nicotine stimulation. Moreover, mutant LRRK2 affects the levels of dopamine receptor D1 on the membrane surface in neuronal cells or animal models. Ultrastructural analysis of PC12-derived cells expressing mutant LRRK2G2019S shows an altered intracellular vesicle distribution. Taken together, our results point to the key role of LRRK2 to control vesicle trafficking in neuronal cells.