Pharmacology of signaling induced by dopamine D1-like receptor activation

Abstract

Dopamine D1-like receptors consisting of D1 and D5 subtypes are intimately implicated in dopaminergic regulation of fundamental neurophysiologic processes such as mood, motivation, cognitive function, and motor activity. Upon stimulation, D1-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 D1-like receptors to multifaceted interactions with various other mediators and receptor systems. The adenylyl cyclase response to dopamine or selective D1-like receptor agonists is reliably associated with the D1 subtype, while emerging evidence indicates that the phosphoinositide responses in native brain tissues may be preferentially mediated through stimulation of the D5 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 D5 coupling to phosphoinositide signaling, the structural features that might enhance pharmacological selectivity for D5 versus D1 subtypes, the mechanism by which dopamine may modulate phosphoinositide synthesis, the contributions of the various responsive signal mediators to D1 or D5 interactions with D2-like receptors, and the spectrum of dopaminergic functions that may be attributed to each receptor subtype and signaling pathway.

Dopamine in the Dorsal Hippocampus Impairs the Late Consolidation of Cocaine-Associated Memory

“…To gain better insight on the molecular mechanisms underlying the persistence of cocaine-associated memories, we next used agonists for D1Rs that are selectively coupled to different intracellular messenger cascades (Undieh, 2010). Whereas the adenylyl cyclase (AC)-selective agonist SKF 83822 given 12 h after three-trial training had no effect on retention tested 7 days after training (Figure 3a To further investigate the hypothesis that persistent cocaine-associated memories depend on D1Rs not coupled to AC, we measured the expression of BDNF, a downstream component of D1Rs/AC/PKA/BDNF/ERK pathway known to be elevated in the dorsal hippocampus 12 h after training in long-lasting fear memories (Bekinschtein et al, 2007;Rossato et al, 2009).…”

“…D1-like receptors are subdivided into D1 and D5 subtypes (Monsma et al, 1990;Sunahara et al, 1991), each of which is expressed in hippocampal neurons. The D5 subtype, presumably the one subtype coupled to PLC (Sahu et al, 2009;Undieh, 2010), is densely expressed in the hippocampus (Laurier et al, 1994) and has a 10-fold higher affinity for DA than does the D1 subtype (Sunahara et al, 1991). We found that SKF 83959 (thought to act specifically at the D5 receptor because it induces the selective activation of PLC intracellular cascade; Undie et al, 1994) had the inhibitory effect we saw with the more generic agonist, whereas SKF 83822, which induces activation of the AC intracellular cascade (O'Sullivan et al, 2004), failed to do so.…”

Dopamine Receptors and Neurodegeneration

“…In fact dopamine receptors co-localize with DARPP-32 in several brain regions [17]. The phosphorylation of DARPP-32 by the PKA in the threonine-34 residue induces the inhibition of the protein phosphatase-1 (PP1) [18], while the phosphorylation of the residue threonine-75 of DARPP-32 by cyclin-dependent kinanse 5 (Cdk5) induces the inhibition of PKA [19,20] causing a feedback loop in the activation of the PKA (Fig. 1).…”

“…D1Rs may elicit an alternate cAMP signaling pathway non-dependent of PKA [20]. The cAMP can activate through the Ras superfamily guanine nucleotide exchange factors (GEFs), which are activators of Ras and Ras-like small G-proteins, specifically has been shown activates Ras-proximate 1 (Rap1) [26] that has been involved in cell polarity and migration [27; 28], Rap1 can also activate MAPK signaling implicated in the phosphorylation of transcription factors such as cAMP response element binding protein (CREB) that is involved in the increased or decreased transcription of genes [29].…”

SKF83959 Is a Potent Allosteric Modulator of Sigma-1 Receptor

“…Unlike the typical D 1 receptor agonists, SKF83959 does not stimulate cAMP production through D 1 -like receptor-mediated activation of G s protein (Andringa et al, 1999a;Makihara et al, 2007;Rashid et al, 2007;Fujita et al, 2010); instead, it selectively activates G q protein through D 1 -like receptor and results in the inositol 1,4,5-triphosphate production (Panchalingam and Undie, 2001;Cools et al, 2002;Jin et al, 2003;O'Sullivan et al, 2004;Ming et al, 2006;Sahu et al, 2009;Undieh, 2010). In animals, the drug was found to increase eye blinking in monkeys and rats and to elicit excellent anti-Parkinsonian effects in the primate model and in the unilateral lesioned rodent model (Gnanalingham et al, 1995;Andringa et al, 1999b;Zhang et al, 2007).…”