D2-like receptors

Functionally, the Dl-like receptors (Dl, D5) are coupled to the G protein Gas and thus can stimulate adenylyl cyclase. The D2-like receptors (D2, D3, and D4) couple to pertussis toxin sensitive G proteins (Gai/0), and consequently inhibit adenylyl cyclase activity. While the Dl-like receptors almost exclusively signal through Gas-mediated activation of adenylyl cyclase, the D2-like receptors have been reported to modulate the activity of a plethora of signaling molecules and pathways. Many of these actions are mediated through the G(3y subunit. Some of these molecules and pathways include the calcium channels, potassium channels, sodium-hydrogen exchanger, arachidonic acid release, and mitogen-activated protein kinase pathways. 

The antipsychotic activity of neuroleptics (D2-like receptor antagonists) has led to the development of many different ligands for the D2 receptor. These drugs... 

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.)...

Table 11.4 shows that clozapine has approximately 10 times higher affinity for the D4 and 5-HT2A-receptors than the D2-receptor and shows a greater occupancy of the 5-HT2 than the D2-like receptors. The other atypical neuroleptic risperidone has a similar affinity for the two D2-like receptors but an affinity for the 5-HT2a-receptor that is just over 3 times lower than for the D2-receptor. Receptor occupancy in vivo shows a similar profile to clozapine. In contrast, haloperidol s affinity for the D4-receptor is just under 3 times lower and over 100 times lower for the 5-HT2a-receptor, with no binding to the latter in vivo. The fractional occupancy of striatal... 

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. 

Narkar, V. A., Hussain, T. and Lokhandwala, M. F. Activation of D2-like receptors causes recruitment of tyrosine-phosphorylated NKA a 1-subunits in kidney. Am. J. Physiol. Renal Physiol. 283 F1290-F1295,2002. 

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... 

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. 

Foote SL, Freedman R, Oliver AP Effects of putative neurotransmitters on neuronal activity in monkey auditory cortex. Brain Res 86 229-242, 1975 Ford DE, Kamerow DB Epidemiologic study of sleep disturbances and psychiatric disorders an opportunity for prevention JAMA 262 1479-1484, 1985 Foreman MM, Gehlert DR, Schaus JM Quinelorane, a potent and selective dopamine agonist for the D2-like receptor family. Neurotransmissions 11 1 -5, 1995 Forn J, Valdecasas FG Effects of lithium on brain adenyl cyclase activity. Biochem Pharmacol 20 2773-2779, 1971... 

The Di-like receptors (Di, D5) couple predominantly to Gs and thus can stimulate adenylyl cyclase, yielding cAMP. The D2-like receptors (D2, D3, D4) couple to Gi/o proteins and may inhibit adenylyl cyclase or modulate many other different signalling molecules and pathways. D3 receptors may also couple to Gs (Obadiah et al. 1999 Ilani et al. 2002). 

A final general observation on Table 1 is that, in several cases, both facilitation through Di-like and inhibition by D2-like receptors have been reported. This holds true for noradrenaline release in rat nucleus accumbens, acetylcholine release in rat striatum, GABA release in rat striatum, nucleus accumbens, and ventral tegmental area (VTA), and glutamate release in rat substantia nigra pars reticulata. 

D2-like receptors couple mainly to Gi/o proteins, as mentioned above. However, there is no direct evidence to support this coupling for the release-modulating autoreceptors. Moreover, the subsequent intracellular signal transduction has never been studied directly in axon terminals. Mouse AtT-20 pituitary cells, which release acetylcholine and adrenocorticotropic hormone, have been used as a model for axon terminals. When expressed in these cells, D3 receptors mediated inhibition of P/Q-type calcium channels and activation of G protein-coupled inward rectifier potassium channels (Kuzhikandathil et al. 1998 Kuzhikandathil and Oxford 1999). Both would explain the autoreceptor-mediated inhibition of dopamine exocytosis. 

As opposed to the disorders of the preceding paragraph, a decrease in dopaminergic transmission may be one of the neurochemical alterations in depression (Dailly et al. 2004). The selective antagonists at D2-like receptors sulpiride and amisulpride, when given at low doses, reduce depression symptoms, presumably by blockade of D2-autoreceptors and enhancement of dopamine release (Racagni et al. 2004). Sulpiride in fact increased the release of [3H]-dopamine in human neocortex slices... 

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