Adenylate cyclase dopaminergic receptors

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.

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. 

Two major second messenger systems have been evolved. When the a-sub-unit is temporarily linked to adenylate cyclase, the enzyme is activated and catalyzes the transformation of ATP to cAMP. This second messenger activates a specific protein kinase, which in turn phosphorylates target proteins in the cell leading to the overall physiological response. Such a pathway is utilized by the /1-adrenoceptor, dopaminergic, and prostaglandin receptors, etc. 

Two types of dopamine receptors have been characterized in the mammalian brain, termed and D2. This subtyping largely arose in response to the finding that while all types of clinically useful neuroleptics inhibit dopaminergic transmission in the brain, there is a poor correlation between reduction in adenylate cyclase activity, believed to be the second messenger linked to dopamine receptors, and the clinical potency of the drugs. This was particularly true for the butyrophenone series (e.g. haloperidol) which are known to be potent neuroleptics and yet are relatively poor at inhibiting adenylate cyclase. 

Dopamine activates adenylate cyclase and phospholipase C (PLC) via a D, receptor and inhibits through a D2 receptor, thereby regulating the production of intracellular second messengers, cAMP, Ca2+, and 1,2-diacylglycerol. D, and D2 receptors are decreased in the striatum of patients with dementia. There is considerable evidence to suggest that intracellular levels of cAMP have a protective role for dopaminergic neurons. Intracellular concentrations of cyclic nucleotides are regulated by cyclic nucleotide phosphodiesterases and CaMPDE, one of the most intensely studied and best-characterized phosphodiesterases. 

All the pharmacological and behavioural effects elicited by dopamine agonists and antagonists in the brain can only be explained if such an interaction occurs at the level of the dopamine receptor (D2 receptor site) the site still remains in search of a function. Bovine parathyroid cells were reported to possess dopamine sites which should be involved in the control of parathormone secretion. However, the very poor pharmacological characterization and the lack of in vivo evidence do not allow to assess the dopaminergic nature of this hormone secretion. Dopamine-sensitive adenylate cyclase is thus not a receptor directly implicated in the dopaminergic neurotransmission it is an enzyme which could have an important role in the control of long term metabolic effects such as the synthesis of neuronal constituents. 

It is incorrect to state that desensitization does not occur in the dopaminergic response of bovine parathyroid cells. We did not, in fact, examine this point directly. Desensitization, however, probably actually does occur at more than one locus in this system. First, the secretory response of the parathyroid cell rapidly becomes refractory to agents such as dopamine and isoproterenol which produce large elevations in cyclic AMP (see ref. 2). Secondly, there is a progressive decrease in cellular cyclic AMP despite the continued presence of dopamine (see Figure 5 in our manuscript) possibly due to desensitization of the receptor-adenylate cyclase compex. 

It has in fact been convincingly demonstrated that the anterior pituitary dopamine receptor is negatively coupled to adenylate cyclase in both tumoral (26), and normal (54) adenohypophysial tissue. Thus, the adenohypophysis cannot be taken, as originally proposed (36), as example of a receptor not coupled to adenylate cyclase. Moreover, it is well known that some dopaminergic responses appear independent of cyclic AMP (74, 75, 76). In order to take into account all the available data, it appears preferable to use the terminology DA+, DA and DA. (54, Fig. 4). Other advantages of this terminology are its clear separation from the nomen-... 

Figure 8. Representation of the interaction between CRF, -adrenergic, and dopaminergic (DA.) receptors in the control of pars intermedia cell activity. The CRF and / -adrenergic receptors stimulate adenylate cyclase activity through interaction with the Ns-GTP-binding component. Dopamine, on the other hand, interacts with the Ni-GTP-binding component, causing inhibition of basal as well as CRF- and f3-adrenergic-induced adenylate cyclase activity.

Rm did not correlate with the intrinsic activity of agonists for their ability to attenuate adenylate cyclase stimulation (36).In that system, only the ratio of K./K appeared to correlate with the intrinsic activity ofLthe alpha-adrenergic agonists. Here, in anterior pituitary membranes constant proportions of both receptor states were evidenced but ratios of 30-200 were found for K./Km for a series of dopaminergic agonists despite the fact that these agonists all appear to display full intrinsic activity in their ability to inhibit prolactin secretion from pituitary cells. 

Activation of neostriatal tyrosine hydroxylase was observed when cyclic AMP was added to high speed supernatants from rat neostriatum (133). Intraventricular injection of dibutyryl cyclic AMP stimulated tyrosine hydroxylation in the neostriatum (134). However, it is still questionable if under physiological conditions this cyclic AMP involvement in the feedback control of tyrosine hydroxylase activity is mediated by presynaptic dopamine receptors or by presynaptic allo-receptors. In addition, if a dopamine sensitive adenylate cyclase is involved in the regulation of neostriatal tyrosine hydroxylase activity it is relevant to know if this adenylate cyclase is linked to a D-1 and/or a D-2 receptor. At this point in time experimental data are not in favour of the presence of a D-l receptor linked to an adeiylate cyclase on the varicosities of dopaminergic neurons in the neostriatum. E.g. concentrations of dopamine agonists stimulating cyclic AMP formation inhibit tyrosine... 

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). 

---