Concluding remarks

Despite the huge amount of work done on dopaminergic systems, and in particular the progress made during the last decade, there is still much to be learnt about dopamine receptors. Additional dopamine receptors may yet be identified and this may shed further light on the ambiguous results found with some dopamine receptor ligands. One of the most interesting features of dopamine receptors, as well as all other GPCRs, is the recently discovered phenomenon of oligomerization of these receptors. Previously, it had been assumed that these receptors functioned as monomers, but evidence for oligomerization of dopamine receptors has now appeared in several systems. Indeed, our laboratory has recently reported the dimerization of dopamine D2 receptor in CHO cells (Armstrong etal. 2001), an observation which confirms previous finding from other groups (Lee et al. 2000; Zawarynski et al. 1998). Evidence of heterodimerization between dopamine D5 receptors and GABAa receptors (Liu etal. 2000) or between dopamine D2 receptors and somatostatin (sst5) receptors (Rocheville et al. 2000) has also been forthcoming. In respect to the former interaction direct binding of the D5 carboxy terminal domain with the second intracellular loop of the GABAa y2s receptor subunit enables mutual inhibitory functional interactions between the two receptor systems. Thus the D5 receptor can dynamically regulate inhibitory synaptic strength through an interaction independent of classical G protein signal transduction cascades. In the case of the sst5/D2 receptor interaction agonists of both receptors promote receptor heterooli-gomerization to form a receptor complex that possesses enhanced functional activity when it is occupied by both agonists. The issue now will be to understand the exact function of these homo- and hetero-oligomers and their possible role(s) in the physiological and pathophysiological conditions. From a strictly mechanistic point of view, it will be of great interest to analyse how different G protein subtypes can affect receptor oligomerization.

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