We are now entering a new era in receptor physiology and pharmacology. Ionotropic and G protein-coupled receptors (GPCRs) cannot be considered anymore as isolated functional units, but as forming part of multimolecular aggregates that include other receptors for other neurotransmitters or neuromodulators. Heteromeric receptor complexes are fundamental for the normal computation of local modules, which can be considered as functional units of the central nervous system. The list of heteromeric GPCR complexes is increasing very fast and, therefore, GPCR heteromerization seems to be the norm. ? During the last years we have found several heteromeric receptor complexes which can be of importance for the understanding of the mechanisms of action of some drugs of abuse, as well as for the application of new therapeutic approaches for drug addiction. Some of those complexes include adenosine receptors. A1 and A2A receptors are the main subtypes of adenosine receptors in the brain and the main targets for caffeine, which is the most consumed psychoactive drug in the world. Adenosine receptor heteromeric complexes are localized in different elements of the striatal spine local module (SSM), which is composed of the dendritic spine of the striatal medium spiny neuron (MSN) and glutamatergic and dopaminergic nerve terminals. A2A receptors form heteromeric complexes with dopamine D2 and metabotropic glutamate mGlu5 receptors. The A2A-D2-mGlu5 receptor complexes are located extrasynaptically and adjacent to the glutamatergic synapse of the dendritic spine of enkephalin MSNs, where they are activated by volume transmission, and their cross-talk within the complex helps to modulate postsynaptic plastic changes at the glutamatergic synapse. By using immunohistochemical, co-immunoprecipitation, electron-microscopy and bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we recently found that A2A receptors also form heteromeric complexes with A1 receptors which are found presynaptically inside the glutamatergic synapse, and the molecular cross-talk between the two receptors in the heteromer exerts a fine-tune modulation of glutamate release. ? End-stage drug addiction, characterized by compulsive drug seeking and relapse, seems to depend mostly on adaptations in cortical glutamatergic projections to the ventral striatum (nucleus accumbens). We have recently demonstrated that, with their ability to form pre- and postsynaptic heteromeric complexes, A2A receptors play a key role in the functional changes of the glutamatergic synapses of the enkephalin MSN during conditions of strong cortico-limbic input. Blockade of A2A receptors with caffeine or a selective A2A receptor antagonist counteracts the striatal activation of cAMP-PKA cascade (phosphorylation of the Ser845 residue of the GluR1 subunit of the AMPA receptor) and MAPK (ERK1/2 phosphorylation) induced by the in vivo stimulation of cortico-striatal afferents. Therefore, A2A receptor antagonists, now in clinical trials of Parkinson?s disease, can be considered as new candidates for drug development aimed at avoiding relapse.? Also in the SSM we have recently demonstrated the existence of a heteromeric receptor complex that includes both GPCRs and ionotropic receptors, the dopamine D2?non-alpha7 nicotinic acethylcholine (nACh) receptor heteromeric complex, which is located in the striatal dopaminergic terminals. With in vivo microdialysis, local perfusion of nicotine in the ventral striatum (shell of the nucleus accumbens) was found to produce a marked increase in the extracellular levels of dopamine, which was completely counteracted by co-perfusion with either a non-alpha7 nACh receptor antagonist or a D2 receptor agonist. This demonstrates the existence of a potent cross talk between GPCRs and ligand-gated ion channels in dopaminergic nerve terminals, with the D2 autoreceptor modulating the efficacy of non-alpha7 nACh receptor-mediated modulation of dopamine release. We further demonstrated physical interactions between beta2 subunits of non-alpha7 nAChs and D2 autoreceptors in co-immunoprecipitation experiments with membrane preparations from co-transfected mammalian cells and rat striatum. These results provide new evidence against the generalized simplistic notion of the neurotransmitter receptor as a single functional entity and, to our knowledge, it is the first example of presynaptic heteromeric receptor complexes that include ligand-gated ion channels and GPCRs that modulate neurotransmitter release.
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