The Dopamine D4 Receptor

The observation that receptors which mediate their signals through heterotrimeric guanosine triphosphate (GTP)-binding proteins (Gproteins) share a considerable amount of sequence similarity has resulted in the rapid molecular characterization of this receptor superfamily. Moreover, it became clear that several receptor families consisted of more receptor subtypes than originally anticipated from pharmacological studies. The dopamine (DA) receptor family, which was originally thought to comprise two receptor types (D1 and D2), includes to date five different DA receptor genes (Bunzow et al. 1988; Dearry et al. 1990; Sokoloff et al. 1990; Sunahara et al. 1990, 1991; Tiberi et al. 1991; Van Tol et al. 1991; Zhou et al. 1990). The major difference between the D1-like receptors D1 and D5/D1B lies in their distribution, but pharmacologically and functionally these two receptors are almost indistinguishable (Sunahara et al. 1991; Tiberi et al. 1991). The D2-like receptor family includes two alternatively spliced forms of the D2 receptor (Dal Toso et al. 1989; Giros et al. 1989; Grandy et al. 1989; Monsma et al. 1989), and the D3 (Sokoloff et al. 1990) and D4 (Van Tol et al. 1991) receptors. Apart from clear differences in distribution profiles, the D2-like receptors also display pharmacological differences. The cloned D2 receptor is able to inhibit adenylyl cyclase (Albert et al. 1990), and is also able to activate several other signal transduction pathways (Elsholtz et al. 1991; Kanterman et al. 1991; Vallar et al. 1990). Moreover, the two alternatively spliced forms of the D2 receptor are not identical in their functional activity (Hayes et al. 1992; Montmayeur et al. 1993).