The class C GABAB receptor is
The class C GABAB receptor is the first known GPCR that was demonstrated to require heterodimerization for functioning. In fact, it is called an obligatory heterodimer (or heteromeric receptor; Ferré et al., 2009) composed by two subunits, GBR1 and GBR2, that have complementary functions in signal transmission (Kniazeff et al., 2011; Moller et al., 2017). While the extracellular domain of GBR1 is responsible for ligand recognition, the transmembrane domain of GBR2 is required for G-protein activation. In addition, GBR2 facilitates the cell surface Benztropine mesylate of GBR1 through coiled-coil interactions in the cytoplasmic region. This heteromer has been crystallized bound to different agonists and antagonists (Geng, Bush, Mosyak, Wang, & Fan, 2013). On the other hand, mGluRs, another members of family C GPCRs, can form non-obligatory heterodimers (or receptor heteromers; Ferré et al., 2009), being the mGlu2-4 the most studied pair due to its physiological interest; concretely, they are involved in control synaptic activity at the level of the cortico-striatal terminals in the striatum (Yin et al., 2014) and at the level of lateral performant path terminals in the dendate gyrus (Moreno-Delgado et al., 2017). Recently, Liu et al. (2017) reported an oriented asymmetry in the activation of this heterodimer that can be controlled with allosteric modulators.
The first ones class A receptors found as heterodimers were reported by Gomes et al. (2000), who identified a heteromer constituted by two subtypes of opioid receptors (μ and δ) in heterologous cells. The same year, Ginés et al. (2000) showed the first heteromer composed of two different receptors, the adenosine A1 and dopamine D1 receptors, in cotransfected fibroblast cells. It is important to mention that many of the heterooligomeric assemblies that have been detected in vivo so far, demonstrate the preponderance of dopamine- and adenosine-containing receptors, indicating their major contribution to various neurological conditions and the full breadth of their therapeutic potential (Farran, 2017).
Dopamine and adenosine in CNS Dopaminergic and purinergic signaling play a pivotal role in neurological diseases with motor symptoms, including Parkinson\'s disease (PD), motor neuron diseases, multiple sclerosis, amyotrophic lateral sclerosis, Huntington disease, Restless Legs Syndrome (RLS) and ataxias (Oliveira-Giacomelli et al., 2018). Dopamine is a pleiotropic compound that acts as a neurotransmitter and a hormone (Borcherding et al., 2011), and plays a key role in numerous CNS processes including attention, behavior and cognition, motor control, motivation and reward, mood, sleep, learning and memory (Puig, Rose, Schmidt, & Freund, 2014; Rubí & Maechler, 2010). Dopamine acts on specific receptors (DRs) belonging to the GPCR family A, which are categorized in two main groups: D1-like (D1R and D5R) and D2-like (D2R, D3R and D4R), that are linked to stimulation (D1R-like) or inhibition (D2R-like) of adenylate cyclase (Cortés, Moreno, Rodríguez-Ruiz, Canela, & Casadó, 2016). DRs directly regulate neurotransmission of other neurotransmitters, release of cAMP, and also cell proliferation and differentiation (Mishra, Singh, & Shukla, 2018). The striatum receives the densest dopamine innervation and contains the highest density of DRs in the brain. D1Rs are expressed selectively by the direct pathway GABAergic spiny projection neurons, whereas D2Rs are expressed by the indirect pathway. Striatal direct and indirect pathways form the functional backbone of the basal ganglia circuit. Both D1R and D2R have distinctive linkages to intracellular signaling cascades and targets, leading to fundamentally different cellular responses to extracellular dopamine (Gerfen & Surmeier, 2011).