Dopamine 2-like receptors

The G-protein coupled receptors modulate intracellular cAMP level, which plays a crucial role in epidermal barrier homeostasis.5 Increase of intracellular cAMP in epidermal keratinocytes by topical application of forskolin delays barrier recovery, while cAMP antagonists accelerate the barrier recovery. Activation of dopamine 2-like receptors (manuscript in preparation), melatonin receptors, or serotonin receptor (type 5-HT1) decreases intracellular cAMP and consequently accelerates the barrier recovery (Figure 15.1), while activation of adrenergic 32 receptors increases intracellular cAMP and delays the barrier repair.6 Barrier disruption induces an increase of the intracellular cAMP level. Thus, topical application of agonists of receptors that reduce intracellular cAMP accelerates the barrier repair. Our results are summarized in Table. 15.1. 

In the periphery, dopamine receptor levels are generally lower than those observed in brain, particularly in comparison to striatal dopamine receptor levels. Due to these low levels, knowledge of receptor distribution in the periphery is not yet comprehensive. Nevertheless, Dl-like receptors have been reported in the parathyroid gland and in the tubular cells of the kidney. D2-like dopamine receptors have also been observed in the kidney. In addition, dopamine D2 and D4 receptors have been found in the adrenal cortex, where they modulate aldosterone secretion. The... 

Neuroleptics or antipsychotics suppress the positive symptoms of schizophrenia such as combativeness, hallucinations and formal thought disorder. Some also alleviate the negative symptoms such as affective blunting, withdrawal and seclusiveness. Neuroleptics also produce a state of apathy and emotional indifference. Most neuroleptics block dopamine D2-receptors but some, like clozapine, also block dopamine D4-receptors or serotonin 5-hydroxytryptamine2A-receptors. 

Hidaka, K, Tada, S, Matsumoto, M, Ohmori, J, Tasaki, Y, Nomura, T, Usuda, S and Yamaguchi, T (1996) In vitro pharmacological profile of YM-43611, a novel D2-like receptor antagonist with high affinity and selectivity for dopamine D3 and D4 receptors. Brit. J. Pharmacol. 117 1625-1632. 

Figure 7.1 Schematic of the prototypical dopaminergic synapse. Pre- and post-synaptic components of a dopaminergic synapse summarizing molecular pathways for dopamine synthesis, metabolism, and second messenger effects following Dl-like or D2-like receptor activation. (See also Plate 6.)...

Govindaiah G., Cox C. (2005). Excitatory actions of dopamine via Dl-like receptors in the rat lateral geniculate nucleus. J. Neurophysiol. 94, 3708-18. 

Le Foil, B., Sokoloff, P., Stark, H., Goldberg, S.R. Dopamine D3 receptor hgands block nicotine-induced conditioned place preferences through a mechanism that does not involve discriminative-stimulus or antidepressant-like effects. Neuropsychopharmacology. 30 720, 2005. 

Sanchez C.J., Bailie T.M., Wu W.R., Li N., Sorg B.A. Manipulation of dopamine dl-like receptor activation in the rat medial prefrontal cortex alters stress- and cocaine-induced reinstatement of conditioned place preference behavior. Neuroscience. 119 497, 2003. 

Acri J., Carter S., Ailing K. et al. Assessment of cocaine-like discriminative stimulus effects of dopamine D3 receptor ligands. Eur. J. Pharmacol. 281 R7, 1995. 

D2-like receptor Dopamine receptors are classified into the Dj-like Gs (Dj and D5 subtypes) and D2-like G (D2, D3 and D4 subtypes) coupled protein receptors. 

The number of D, and D2 receptors can be modulated by antagonists 222 Dopamine D2-like receptors appear to mediate the actions of antipsychotic drugs 222... 

Dopamine receptors are found primarily in brain, although they also exist in kidney [33]. Two subtypes of dopamine receptor were initially identified based primarily on differences in their drug specificities and signaling mechanisms. D receptors were found to stimulate adenylyl cyclase activity, while D2 receptors inhibited this enzyme (Fig. 12-6). Subsequently, multiple Dr and D2-like receptors were identified by molecular cloning (Table 12-3) [33], All dopamine receptor subtypes are... 

Baik, J. H., Picetti, R., Saiardi, A. etal. Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature 377 424—428,1995. 

Dopamine acts on G-protein-coupled receptors belonging to the D1 -family of receptors (so-called D1-like receptors , or DlLRs, comprised of Dl- and D5-receptors), and the D2-family of receptors ( D2-like receptors , or D2LRs comprised of D2-, D3- and D4-receptors). Dl LRs stimulate adenylate cyclase activity and, possibly, also phosphoinosit-ide hydrolysis, while D2LRs reduce adenylate cyclase activity. In the striatum, DlLRs are predominately associated with medium spiny neurons of the direct pathway, while D2LRs have been found as autoreceptors on dopaminergic terminals, as heteroreceptors on cholinergic interneurons, and on indirect pathway neurons. In the SNr, DlLRs are located on terminals of the direct pathway projection, while D2LRs appear to function as autoreceptors. 

Saurer, T. B. et al., Morphine-induced alterations of immune status are blocked by the dopamine D-2-like receptor agonist 7-OH-DPAT, J. Neuroimmunol., 148, 54, 2004. 

A wide range of mammalian proteins have been expressed in S. pombe. In a successful example, the human lipocortin I comprised 50% of the total soluble proteins in yeast cells and showed high activity, indicating that the post-translational modifications were mammalian-like [104]. Membrane proteins including cytochrome P450 were expressed at ten times the levels of those in other yeast systems [105]. Also, GPCRs have been expressed in S. pombe, where the human dopamine D2 receptor was correctly inserted into the yeast cell membrane and demonstrated expression levels three times those of S. cerevisiae [106]. 

In vitro studies suggest that the GRK4 SNPs impair the function of receptors, increase blood pressure, and impair the diuretic and natriuretic effects of dopamine Dj-like agonist stimulation. Inappropriate desensitization of the dopamine D, receptor in renal proximal tubules in hypertension may result in the decreased ability of the kidney to eliminate a sodium chloride load—a key risk factor in the development of hypertension. 

Caveats aside, the five dopamine receptors remain candidates in disease. The pharmacological properties that have been used to group them into dopamine Dj-like and dopamine D -like receptors may also be useful to consider when surveying the dopamine receptor gene association studies. For the most part, the D -like dopamine receptors Dj (50-52) and Dj (53) have not been as widely associated with disease as the D dopamine receptors. The D -like receptors D (54), D3 (55), and D (56) have similar dopamine sensitivities and are much more polymorphic than the Dj-like receptors (49,57). 

The dopamine D -like receptor polymorphisms include SNPs, variable-number tandem repeats (VNTRs), and splice variants (58,59). The polymorphic forms of the dopamine D receptor, for example, manifest as variable numbers of 48-bp repeat sequences (denoted D j to D., ) (49). 

The efficacy of antipsychotics, with respect to dopamine receptors, results mostly from blockade of D -like receptors. Binding of the classical antipsychotics (e.g., bromocriptine and raclopride), however, is about two orders of magnitude stronger at D receptors compared with D receptors. The atypical antipsychotics,... 

By contrast, studies of the dopamine D -like receptors have found evidence for the association of the receptor with disease (66) these studies have been replicated (41,42). From among the multitude of these studies, only selected examples are reviewed here. For example, evidence both for and against the association of the dopamine D -like receptors with schizophrenia has been reported. Polymorphisms of the dopamine receptor, including the third intracellular loop VNTR, alter dopamine receptor expression. In addition to association with schizophrenia (3,67-70), the dopamine polymorphisms have been associated with the genetic basis of the variable efficacy of antipsychotics such as clozapine (or neuromuscular toxicity—tardive dyskinesia) (69,71,72). Similarly, promoter SNPs have been associated with altered clozapine efficacy (67,68,73). 

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