Pharmacology of signaling induced by dopamine D1-like receptor activation

Dopamine D 1 -like receptors consisting of D 1 and D 5 subtypes are intimately implicated in dopaminergic regulation of fundamental neurophysiologic processes such as mood, motivation, cognitive function, and motor activity. Upon stimulation, D 1 -like receptors initiate signal transduction cascades that are mediated through adenylyl cyclase or phosphoinositide metabolism, with subsequent enhancement of multiple downstream kinase cascades. The latter actions propagate and further amplify the receptor signals, thus predisposing D 1 -like receptors to multifaceted interactions with various other mediators and receptor systems. The adenylyl cyclase response to dopamine or selective D 1 -like receptor agonists is reliably associated with the D 1 subtype, while emerging evidence indicates that the phosphoinositide responses in native brain tissues may be preferentially mediated through stimulation of the D 5 receptor. Besides classic coupling of each receptor subtype to specific G proteins, additional biophysical models are advanced in attempts to account for differential subcellular distribution, heteromolecular oligomerization, and activity-dependent selectivity of the receptors. It is expected that significant advances in understanding of dopamine neurobiology will emerge from current and anticipated studies directed at uncovering the molecular mechanisms of D 5 coupling to phosphoinositide signaling, the structural features that might enhance pharmacological selectivity for D 5 versus D 1 subtypes, the mechanism by which dopamine may modulate phosphoinositide synthesis, the contributions of the various responsive signal mediators to D 1 or D 5 interactions with D 2 -like receptors, and the spectrum of dopaminergic functions that may be attributed to each receptor subtype and signaling pathway.