The striatum is the main input structure of the basal ganglia, which are subcortical structures involved in the processing of information related to the performance and learning of complex motor acts. It is widely accepted that dopamine receptor subtypes, which are fundamental for motor control and are implicated in numerous neuropsychiatric disorders, are largely segregated in the two subtypes of medium spiny neurons (MSNs), 4 the most populated neuronal type in the striatum. Dopamine D 2 receptors (D 2 Rs) are mostly localized in the striatopallidal MSNs, which express the peptide enkephalin and which gives rise to the indirect striatal efferent pathway, whereas dopamine D 1 receptors (D 1 Rs) are mostly expressed by the striatonigral MSNs, which express substance P and dynorphin and constitute the direct striatal efferent pathway (1, 2). Dopaminergic drugs activate the ERK transduction pathway, which is involved in basic physiological processes and in synaptic plasticity (3). In the dopamine-depleted striatum, ERK signaling is implicated in the development of L-DOPA-induced dyskinesia. Thus, in dopamine-denervated mice, L-DOPA activates ERK signaling specifically in D 1 Rs containing striatonigral MSNs but not in D 2 Rs containing striatopallidal MSNs (4). This regulation may result in ERKdependent changes in striatal plasticity leading to dyskinesia.Histamine is an important regulatory transmitter in the nervous system involved in the sleep/wake cycle, attention, memory, and other functions. Four histamine receptor types (H 1 R-H 4 R) have been cloned. H 3 Rs are expressed in abundance in the brain and high densities are particularly found in the striatum (5-7). H 3 Rs were first identified as autoreceptors (8), but they were later found to act as heteroreceptors (9). * This study was supported by Grants SAF2008-00146, SAF2008-03229-E, SAF2009-07276, SAF2006-08240, and SAF2009-12510

It was inferred that different molecular mechanisms were involved in GPCR homo-and heteromerization. For family C GPCRs, disulfide bonds between extracellular domains as well as coiled-coil interactions between C-terminal domains seem to be necessary for the formation of functional homomeric or heteromeric receptors (8). For oligomerization of family A GPCRs, the helical transmembrane (TM) domains seem to be particularly important (7, 9 -15). In this study, by using mutated A 2A , CB 1 , and D 2 receptors, we investigated the relevance of electrostatic interactions (16) between intracellular domains in the determination of the quaternary structure of GPCR heteromers between A 2A , CB 1 , and D 2 receptors. Our initial goal was to obtain evidence for multiple intracellular interactions in the A 2A -CB 1 -D 2 receptor heteromultimer. Significantly, the same intracellular domains involved in A 2A -CB 1 -D 2 receptor heteromultimerization were also involved in