D(3) dopamine receptor (D(3)R) is expressed mainly in parts of the brain that control the emotional behaviors. It is believed that the improper regulation of D(3)R is involved in the etiology of schizophrenia. Desensitization of D(3)R is weakly associated with G protein-coupled receptor kinase (GRK)/beta-arrestin-directed internalization. This suggests that there might be an alternative pathway that regulates D(3)R signaling. This report shows that D(3)R undergoes robust protein kinase C (PKC)-dependent sequestration that is accompanied by receptor phosphorylation and the desensitization of signaling. PKC-dependent D(3)R sequestration, which was enhanced by PKC-beta or -delta, was dynamin dependent but independent of GRK, beta-arrestin, or caveolin 1. Site-directed mutagenesis of all possible phosphorylation sites within the intracellular loops of D(3)R identified serine residues at positions 229 and 257 as the critical amino acids responsible for phorbol-12-myristate-13-acetate (PMA)-induced D(3)R phosphorylation, sequestration, and desensitization. In addition, the LxxY endocytosis motif, which is located between residues 252 and 255, was found to play accommodating roles for PMA-induced D(3)R sequestration. A continuous interaction with the actin-binding protein 280 (filamin A), which was previously known to interact with D(3)R, is required for PMA-induced D(3)R sequestration. In conclusion, the PKC-dependent but GRK-/beta-arrestin-independent phosphorylation of D(3)R is the main pathway responsible for the sequestration and desensitization of D(3)R. Filamin A is essential for both the efficient signaling and sequestration of D(3)R.

Among the characterized dopamine receptor subtypes, D₂ receptor (D₂R) and D₃ receptor (D₃R) are the main targets of neuroleptics that are currently in use. In particular, D₃R is closely related to the etiology of schizophrenia and drug addiction. The spatial expression patterns of D₂R and D₃R are distinct in certain areas of the brain. D₂R are heavily expressed in the regions responsible for motor functions, whereas D₃R are more selectively expressed in the limbic regions, which are associated with cognitive and emotional functions. Therefore, disturbances in the motor and endocrine functions, which are the most serious problems caused by the current neuroleptics, are likely to result from the non-selective blockade of D₂R. Selective regulation of D₃R is needed to separate the desired therapeutic activities from unwanted side effects that result from promiscuous blockade of other receptors. D₂R and D₃R possess high sequence homology and employ similar signaling pathways, and it is difficult to selectively regulate them. In this review, we discuss the signaling mechanisms, intracellular trafficking, and desensitization properties of D₂R and D₃R. In addition, the proteins interacting with D₂R or D₃R are discussed in relation to their roles in the regulation of receptor functions, followed by the current status of the development of selective D₃R ligands.

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Allergic and inflammatory responses are functionally linked through a cascade of signaling events that connect the aggregation of the high affinity IgE receptor (FcHRI) on mast cells and the initiation of cyclooxygenase-2 (COX-2) expression. In this study, we identified the cis-acting elements in the cox-2 promoter that control the expression of COX-2 in RBL-2H3 mast cells. We also investigated how the inflammatory reaction is controlled by the allergic reaction by determining the signaling components employed by FcHRI in the transcriptional regulation of cox-2. Among cis-acting components present in the cox-2 promoter, the CREB binding site, as well as the AP-1 and proximal NF-IL6 binding sites to a lesser extent, were required for the transcriptional regulation of the cox-2 promoter. However, NF-NB and Ets-1 binding sites exerted negative effects on the cox-2 promoter activity. Among the signaling components of FcHRI, Fyn, PI 3-kinase, Akt, and p38 MAPK positively mediated the COX-2 expression. Conventional PKCs and atypical PKCs exerted opposite regulatory effects on the cox-2 promoter activity. Blockade of MEK/ERK pathway inhibited the cox-2 promoter activity and the COX-2 expression. These results reveal intricate functional interactions among different cis-acting elements in the transcriptional regulation of cox-2. FynoPI 3-kinaseoAkt pathway directly stimulate. On the other hand, LynoSyk pathway exerts auxiliary or compensatory influences on COX-2 expression via PKC and MEK/ERK.