Original articles
Evidence for Adenosine/Dopamine Receptor Interactions: Indications for Heteromerization

https://doi.org/10.1016/S0893-133X(00)00144-5Get rights and content

Abstract

Evidence has been obtained for adenosine/dopamine interactions in the central nervous system. There exists an anatomical basis for the existence of functional interactions between adenosine A1R and dopamine D1R and between adenosine A2A and dopamine D2 receptors in the same neurons. Selective A1R agonists affect negatively the high affinity binding of D1 receptors. Activation of A2A receptors leads to a decrease in receptor affinity for dopamine agonists acting on D2 receptors, specially of the high-affinity state. These interactions have been reproduced in cell lines and found to be of functional significance. Adenosine/dopamine interactions at the behavioral level probably reflect those found at the level of dopamine receptor binding and transduction. All these findings suggest receptor subtype-specific interactions between adenosine and dopamine receptors that may be achieved by molecular interactions (e.g., receptor heterodimerization). At the molecular level adenosine receptors can serve as a model for homomeric and heteromeric protein–protein interactions. A1R forms homodimers in membranes and also form high-order molecular structures containing also heterotrimeric G-proteins and adenosine deaminase. The occurrence of clustering also clearly suggests that G-protein- coupled receptors form high-order molecular structures, in which multimers of the receptors and probably other interacting proteins form functional complexes. In view of the occurrence of homodimers of adenosine and of dopamine receptors it is speculated that heterodimers between these receptors belonging to two different families of G-protein-coupled receceptors can be formed. Evidence that A1/D1 can form heterodimers in cotransfected cells and in primary cultures of neurons has in fact been obtained. In the central nervous system direct and indirect receptor–receptor interactions via adaptor proteins participate in neurotransmission and neuromodulation and, for example, in the establishment of high neural functions such as learning and memory.

Section snippets

Dopamine-adenosine interactions in the central nervous system

Adenosine is an endogenous nucleoside acting as a neuromodulator in the central nervous system. Its actions are mediated by adenosine receptors, four of which have been cloned and pharmacologically characterized: A1, A2A, A2B and A3 (Fredholm et al. 1994). Among those four subtypes A1 and A2A are the main targets of the behavioral effects occurring in animals treated with adenosine analogs Ferré et al. 1992, Ferré et al. 1993, Ferré et al. 1997, Fredholm 1995. Caffeine, as an example of an

Adenosine receptors as a model for homomeric and heteromeric protein–protein interactions

The work of Franco and colleagues on A1 adenosine receptors has provided a better understanding of how ligand binding and signal transduction is affected by homotypic and heterotypic protein–protein interactions Franco et al. 1996, Franco et al. 1997, Ginés et al. 2000, Sarrió et al. 2000.

The binding of [3H]-2-chloroadenosine to A1 receptors present in rat brain membranes was first studied in two laboratories. Basically, depending upon the absence or presence of exogenous adenosine deaminase

Dimers and clusters of gpcrs

Since the description of the existence of homodimers for 5HT1B, D1, D2 (Ng et al. 1993, Ng et al. 1994a, Ng et al. 1994b, 1995) and A1 receptors (Ciruela et al. 1995) a number of reports have described the occurrence of homodimers for a variety of GPCRs. In fact it now seems that any member of the GPCR superfamily can be present in form of dimers in the plasma membrane. To our knowledge reports on the existence of dimers have been disclosed for dopamine (Ng et al. 1993, Ng et al. 1994a, Ng et

Dopamine-adenosine receptor– receptor interactions

Some of the functional interactions between dopamine and adenosine can be explained by downstream interactions. Thus the A1/D1 receptor antagonism at the level of the cAMP formation can be easily explained by the fact that G-proteins for A1R and D1R are differently coupled to adenylate cyclase. However, some of the functional interactions occur even in acute treatments (see above) which suggested that a direct interaction may occur. Due to the occurrence of homodimers of adenosine and of

Homo- and heteromerization of gpcr: understanding the nervous system

In 1999 the first reports on heteromerization involving GPCR started to appear in the literature. They corresponded to heterodimerization among receptors for the same ligand. Heterodimers consisting of two subtypes of opioid receptors (κ and δ) have a pharmacological profile that differs from that corresponding to each of the receptor subtypes when expressed alone (Jordan and Devi 1999). The case of heterodimerization of GABABR1 and GABABR2 receptors is paradigmatic since cells only express

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