Lately using receptor TM peptides BiFC and PLA
Lately, using receptor TM peptides, BiFC and PLA experiments, we have also obtained experimental evidence for the tetrameric structure of A1R–D1R, which explains the canonical interaction on Gi and Gs, respectively (Fig. 2). We have demonstrated for the first time the presence of this heterotetramer in striatal tissue (manuscript in preparation), in addition to in spinal motoneurons (Ferré, Quiroz, et al., 2018; Rivera-Oliver et al., 2018). The spinal A1R–D1R heterotetramer could explain the recently demonstrated spinally-generated caffeine-induced locomotor activation in rats (Acevedo et al., 2016), and highlights the mechanism involved in the spinal component of RLS (Trenkwalder & Paulus, 2010).
Interestingly, Cordomí, Navarro, Aymerich, and Franco (2015) previously proposed for several tetrameric GPCRs heteromers coupled to two G proteins, the existence of “linear” and “zig-zagged” tetramers. In these structures the two G proteins may potentially bind either to the inner or outer protomers, giving rise to “in–in,” “in–out,” or “out–out” possibilities. These arrangements are compatible with available structural data and current knowledge of signal transduction, and are more permissive than the formation of “compact” tetramers that obstruct G protein binding due to excessive crowding at the cytoplasmic region. Moreover, these structures may be useful to reveal how one receptor may allosterically modulate another receptor, and can explain how two G proteins can communicate with each other and affect heteromer-mediated signaling (Cordomí et al., 2015).
The current accumulated knowledge of the biochemical properties of the recently detected A2AR–D2R heterotetramer-AC5 complex offers new therapeutic possibilities for PD, schizophrenia, substance use disorder and other neuropsychiatric disorders with dysfunction of dorsal or ventral striatopallidal WM-2474 (Ferré, Bonaventura, et al., 2018). Moreover, given their involvement in the modulation of crucial physiological processes, GPCR heteromers could constitute important therapeutic targets for a wide range of diseases including obesity, pre-eclampsia, pain, alterations of endocrine regulation, liver fibrosis, acromegaly, pancreatic cancer, and several CNS disorders with abnormal movements such as RLS and SCI.
Conclusion Two decades ago, it was described the antagonistic modulatory role of adenosine on dopaminergic transmission, which was largely dependent on the allosteric interactions between specific subtypes of adenosine and dopamine GPCRs. Nowadays, the modulations between A2AR and D2R and between A1R and D1R are well established in the brain striatum, where these receptors have been detected in situ forming heteromeric complexes. These GPCR heteromers are between the very few that fit to all three criteria to be considered true heteromers. All of these facts suggest that AR-DR heteromers are potential therapeutic targets for the treatment of motor dysfunctions in aging, PD, SCI or PLMS in RLS. We have focused this essay on the A1R–D1R heteromer as a potential target for RLS treatment not only because it has been reported an A1R downregulation in animals with BID but also since there is an up-regulation of the D1R system after long-term use of D3R drugs that leads to augmentation in RLS patients and, in addition, due to the fact that this heteromer is also expressed in spinal cord motoneurons. The A1R–D1R heteromer, as reported for other receptors, has a basic heterotetrameric structure formed by a homodimer of A1R coupled to Gi and a homodimer of D1R coupled to Gs. A good knowledge about the allosteric interactions within this complex would allow the pharmacological control of the dopamine-adenosine modulations found altered in several motor pathologies as PLMS in RLS. Thus, depending on the striatal or spinal cord pathology, different drugs acting on the A1R–D1R heterotetramer could modulate D1R-mediated excitability of the direct-pathway in striatal spiny neurons or of the spinal motoneurons. In this context, A1R agonists may counteract D1R activation and this could be useful for the treatment of RLS and other hyperactivity-like diseases (Fig. 2). In contrast, A1R antagonists may promote a better D1R activation and could be useful for the treatment of PD, SCI and aging motor deficits.