Extracellular signal-regulated kinase 1 (ERK1) 1 and ERK2 (p44 ERK and p42 ERK ) are key cellular components that control cell proliferation and differentiation (1). The regulation of ERK through G protein-coupled receptors (GPCRs) is a complicated process. Various signaling components play different roles in ERK activation depending on the GPCR and cell types involved (2).There has been substantial progress in the understanding of cellular events that link the activation of GPCR and ERK (for review, see Ref. 1). These signaling events can be classified into several distinct pathways. They include: (i) Ras-dependent activation of ERK via transactivation of receptor-tyrosine kinases (RTKs) such as EGFR, (ii) Ras-independent ERK activation via protein kinase C (PKC) that converges with RTK signaling at the Raf level (iii) activation or inhibition of ERK via the cAMP/ protein kinase A (PKA) pathway, in which the direction of regulation depends on the type of Raf involved, and (iv) the recently substantiated ␤-arrestin-mediated pathway proven in certain classes of GPCRs (3). However, it should be mentioned that these signaling pathways are deduced from the limited sets of individual receptors or cell types, and more extensive and systemic studies are needed for these signaling models to be generalized (4). Among all the dopamine receptor subtypes characterized, it is generally accepted that D 2 R and D 3 R are related to schizophrenia. Possibly because of high similarity in their amino acid composition (46% overall amino acid homology and 78% identity in the transmembrane domains) (5), D 2 R and D 3 R share most signaling pathways such as adenylyl cyclase, extracellular acidification, mitogenesis, ERK activation, inhibition of dopamine synthesis, and ion channel regulation (K ϩ , Ca 2ϩ ) (for review, see Ref. 6). Furthermore, recent studies show that although D 3 R is more densely expressed in the limbic area, mesencephalic dopaminergic neurons express both D 2 R and D 3 R (7-9). Because D 2 R and D 3 R are virtually the same in functional aspect and are expressed in the same cells, it can be speculated that signaling routes or regulatory mechanisms for functions of effectors could be different. To address this issue, we decided to focus on a specific cellular function and conduct a detailed study on signaling mechanisms in order to see if their signaling or regulatory pathways differ. ERK activation was selected as a model experimental system, because GPCRmediated ERK regulation consists of multiple complex steps, which are relatively well established. D 2 R-mediated ERK activation has been reported from different cell types. It is pertussis toxin (PTX)-sensitive and partially blocked by the dominant negative mutant of Ras, N17Ras, in