Adenylate cyclase coupling with dopamine receptors

Coupling of dopamine receptors with adenylate cyclase DAj., DA and DAq receptors... 

Another important property of dopamine is its ability to inhibit sympathetic nerve function by interacting with presynaptic dopaminergic receptors to decrease norepinephrine release (10). These receptors are not adenylate cyclase coupled and have been classified as D-2 (8). Activation of cardiac presynaptic dopamine receptors causes bradycardia, and of vascular presynaptic dopamine receptors passive vasodilation, the magnitude of which will depend on the contribution of adrenergic activity to maintaining heart rate and vascular smooth muscle tone (11,12). 

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. 

Other protein kinases may indirectly influence the activation of NF-kappap. For example, in contrast to the pro-inflammatory effects typically observed with activation of kinases, the elevation ofcAMP activates PKA and blocks transcription of iNOS mRNA [51,178, 229, 230]. Astrocytes contain a variety of NT receptors that are coupled to Gs-adenylate cyclase [231] and, either activation of P-adrenergic/dopamine receptors or employing agents that increase cAMP, such as forskolin (adenylate cyclase activator), PDE inhibitors [i.e. pentoxifylline], dibutyrl cAMP, or 8-bromo cAMP can attenuate lipopolysaccharide (LPS)/cytokine activated iNOS mRNA in microglia, astrocytes and a number of other cell types [51,176,177,178, 232-237]. In contrast, agents that suppress the intracellular concentration of cAM P such as H-89 and Rp-cAM P are pro-... 

Ga-GDP has no affinity for the effector protein and reassociates with the p and Y subunits (A). G-proteins can undergo lateral diffusion in the membrane they are not assigned to individual receptor proteins. However, a relation exists between receptor types and G-protein types (B). Furthermore, the a-subunits of individual G-proteins are distinct in terms of their affinity for different effector proteins, as well as the kind of influence exerted on the effector protein. G -GTP of the Gs-protein stimulates adenylate cyclase, whereas G -GTP of the Gr protein is inhibitory. The G-protein-coupled receptor family includes muscarinic cholinoceptors, adrenoceptors for norepinephrine and epinephrine, receptors for dopamine, histamine, serotonin, glutamate, GABA, morphine, prostaglandins, leukotrienes, and many other mediators and hormones. 

These smoked substances interact with the brain s own cannabinoid receptors to trigger dopamine release from the mesolimbic reward system. There are two known cannabinoid receptors, CB1 (in the brain, which is coupled via G proteins and modulates adenylate cyclase and ion channels) and CB2 (in the immune system). The CB1 receptors may mediate not only marijuana s reinforcing properties, but also those of alcohol. There is also an endogenous cannabinoid system (the brain s own marijuana) capable of activating these cannabinoid receptors functionally. These ert-docannabinoids are synthesized by neurons and inactivated by reuptake systems and enzymes in both neurons and glia. 

It is very likely an inaccuracy to call the D-l dopamine receptor an enzyme. Because of the effects of guanine nucleotides on dopamine-stimulated adenylate cyclase, it is likely by analogy with other receptors (i.e. the 3 receptor) that the D-l receptor is a distinct molecular entity which is coupled to adenylate cyclase by a guanine nucleotide binding subunit. Proof of this point, of course, will require physical separation of these entities. 

Figure 4. Representation of the classification of the dopamine receptor based on its coupling with adenylate cyclase activity. DA+ receptors (left) are coupled to adenylate cyclase through the Ns GTP-binding protein (91) with secondary activation of adenylate cyclase. DA. receptors (middle) are coupled through the Ni GTP-binding protein, thus resulting in inhibition of cyclic AMP formation. DA0 receptors (right) are those uncoupled to cyclic AMP formation, the example being possibly some autoreceptors on nigrostriatal dopaminergic neurons.

Enjalbert A, Bockaert J (1983) Pharmacological characterization of the D2 dopamine receptor negatively coupled with adenylate cyclase in rat anterior pituitary. Mol Pharmacol 23 576-584. 

Seaquist ER, Armstrong MB, Gettys TW, Walseth TF (1995) Somatostatin selectively couples to G(o) alpha in HIT-T15 cells. Diabetes 44 85-89 Senaris RM, Humphrey PP, Emson PC (1994) Distribution of somatostatin receptors 1, 2 and 3 mRNA in rat brain and pituitary. Eur J Neurosci 6 1883-1896 Senogles SE (1994) The D2 dopamine receptor isoforms signal through distinct Gja proteins to inhibit adenyl cyclase a study with site-directed mutant GiO proteins. J Biol Chem 269 23120-23127... 

By raising the base level of cAMP and thus increasing the sensitivity of the assay, Florijn et al. (1992) have demonstrated the presence of an ACTH and/or MSH receptor coupled to adenylate cyclase in the brain. The striatum also selects cAMP as a second messenger (Wiegant et al, 1979, 1981 Florijn et al, 1991) but the melanocortins preferentially interact with striatal dopamine D2 receptors (Florijn et al, 1992). 

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