Di dopamine receptor

Fig. 7.5 Schematic flowchart of the competitive MS-binding assay quantifying the nonbound marker employed for dopamine Di receptors. After incubation of the target (Di receptor) in presence of the marker (SCH 23390) and a test compound, the binding samples are centrifuged to separate bound from nonbound marker. The nonbound marker in the resulting supernatant is quantified by LC-ESI-MS/MS without further sample preparation.

Fig. 7.6 Nonbound SCH 23390 in a competitive MS binding assay for dopamine Di receptors monitored at a transition from 288.1 91.2 m/z from binding samples without or with (+)-butaclamol. Intensity (/) is shown (a) without (+)-butaclamol, (b) with 30 nM (+)-butaclamol, (c) with 10 pM (+)-butaclamol. (a-c) Representative chromatograms after HPLC separation (RP8 column solvent CH3CN/0.1% HCOOH in H2O 1 1 300 pL min ).

Fig. 7.7 Representative binding curve obtained by nonlinear regression from a competitive MS binding assay for dopamine Di receptors, in which (+)-butaclamol competes with SCH 23390 as marker. The points describe nonbound SCH 23390 quantified by LC-ESI-MS/MS. Data reflect means (+s) from binding samples, each performed in quadruplicate.

Iodinated radiographic contrast media can cause acute renal insufficiency, perhaps as a result of reduced renal blood flow, an intrarenal osmotic effect, or direct tubular toxicity (58). Diuretics, calcium channel blockers, adenosine receptor antagonists, acetylcysteine, low-dose dopamine, the dopamine Di receptor agonist fenoldopam, endothelin receptor antagonists, and captopril have all been used to prevent contrast nephropathy. 

Fenoldopam is a newer peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension. It acts primarily as an agonist of dopamine Di receptors, resulting in dilation of peripheral arteries and natriuresis. The commercial product is a racemic mixture with the (R)-isomer mediating the pharmacologic activity. 

The presence and density of Di receptors have been investigated in several studies (Aiso et ah, 1987 Dawson et ah, 1988 Richfield et ah, 1989 Huang et al., 1992, Levey et ah, 1993 Yung et al., 1995). Figure 22 depicts the relative density of dopamine Di receptor binding sites at selected representative levels of the rat brain in structures with high and medium concentration of this receptor. 

Zhuang X, Belluscio L, Hen R (2000) Goifa mediates dopamine Di receptor signaling. J Neurosci 20(RC91) l-5. 

Baldwin AE, Sadeghian K, Kelley AE (2002) Appetitive instrumental learning requires coincident activation of NMDA and dopamine DI receptors within the medial prefrontal cortex. J Neurosci 22 1063-1071. 

Fenu S, Di Chiara G (2003) Facilitation of conditioned taste aversion learning by systemic amphetamine role of nucleus accumbens shell dopamine DI receptors. Eur J Neurosci 75 2025-30. 

Fenu S, Bassareo V, Di Chiara G (2001) A role for dopamine DI receptors of the nucleus accumbens shell in conditioned taste aversion learning. J Neurosci 27 6897-6904. 

Gerrits MA, Ramsey NF, Wolterink G, van Ree JM (1994) Lack of evidence for an involvement of nucleus accumbens dopamine DI receptors in the initiation of heroin self-adrninistration in the rat. Psychopharmacol 774 486-494. 

Onaka T, Torigoe H, Yagi K (1992) A dopamine DI receptor antagonist, SCH 23390, selectively blocks vasopressin release after noxious stimuli in the rat. Neurosci Letts 736 157-160. 

Knable MB, Hyde TM, Murray AM, Herman MM, Kleinman JE (1996) A postmortem study of frontal cortical dopamine DI receptors in schizophrenics, psychiatric controls, and normal controls. Biol Psychiatry 40 1191-1199. 

Compound 79 does not induce an effect on the release of dopamine from the striatum (Figure 5. ID). The binding data together with literature data suggest that this compound is a partial dopamine D2 receptor agonist and a dopamine Di receptor antagonist.261 Therefore, the present pharmacodynamic method was not suitable to determine the relative oral bioavailability. 

Blanchet, P.J. Grondin, R. Bedard, P.J. Shiosaki, K. Britton, D.R. (1996) Dopamine Di receptor desensitization profile in MPTP-lesioned primates. Eur. J. Pharmacol. 309, 13-20. 

Seiler, M.P. and Markstein, R. (1984) Further characterization of structural requirements for agonists at the striatal dopamine D2 receptor and a comparison with those at the striatal dopamine Di receptor. Studies with a series of monohydroxyaminotetralins on acetylcholine release from rat striatum. Mol. Pharmacol. 26,452-457. 

The desensitization motifs in the dopamine Di receptor, as an example, may be at least partly located in the proximal carboxyl tail of the receptor [137], It is likely that this region interacts with portions of the third intracellular loop in order to promote desensitization. These structures may also be involved in recycling and trafficking of inactivated receptors [162, 163], A portion of the proximal carboxyl tail of the dopamine Di receptor may contain some of the residues necessary, but not sufficient on their own, for GRK2 mediated desensitization. A motif consisting of a serine or threonine preceded by an acidic amino acid may define the GRK2 recognition sequence [163],... 

For the dopamine Di receptor, the 360Thr and preceding 359Glu may play a role (Fig. 3). Normal desensitization of the... 

For the dopamine Di receptor, normal internalization may be dependent on distal carboxyl terminal residues (see Fig. 3) that are independent of the 360Thr that may be required for desensitization (see Fig. 4c, d). Therefore some, although not all, GPCRs show radical dissociation between desensitization and internalization. This is found not only in the dopamine Di receptor [137] but also in the NTormyl peptide [149] and the M2 muscarinic [170] receptors. 

The GRK4 SNPs include Arg65Leu, Alal42Val, and Ala486Val. Dopamine Di receptor-mediated cAMP production is reported to be markedly impaired by these variants. Expression of these SNPs is also associated with increased basal phosphorylation of the dopamine Di receptor. This suggests that increased basal phosphorylation of the dopamine Di receptor by GRK4 may be associated with the decreased responsiveness of the dopamine Di receptor in hypertension [202, 203],... 

In vitro studies suggest that the GRK4 SNPs impair the function of D receptors, increase blood pressure, and impair the diuretic and natriuretic effects of dopamine D like agonist stimulation. Inappropriate desensitization of the dopamine Di 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. 

The high sequence conservation of the dopamine D4 receptor may reflect its importance to central nervous system function as is also suggested by its wide expression in the brain and relatively high affinity for dopamine. The dopamine Di receptor gene is essentially nonpolymorphic, in its exon-intronic regions [41], A 5 untranslated region (UTR) promoter SNP, however, has been associated with a number of neuropsychiatric disorders and drug response phenotypes. 

With respect to the dopamine D like receptors, including the dopamine D5 receptor (which is ten times more sensitive to dopamine and has a much more narrow tissue expression than the dopamine Di receptor), very few associations of coding variants with disease have been identified [41, 42], Associations of noncoding promoter region SNPs, however, have been associated with various disease phenotypes. These findings, while far from unanimous, suggest associations with bipolar disorder, alcoholism, and attention-deficit disorder, to name a few [60-65]. 

The most frequent posttranslational modifications for GPCRs are N-glycosylation at the N-terminus and external loop Asn-X-Ser/Thr sequences (human calcitonin receptor-like receptor [61] and un,-adrenergic receptor [62]), pabnitoylation (human dopamine Di receptor [63]), and phosphorylation ( 2 adrenergic receptor [64]). 

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