The cannabinoid CB receptor interacts with the angiotensin AT receptor. Overexpression of AT-CB receptor heteromers in the striatum of 6-hydroxydopamine hemilesioned rats.

It is of particular interest the potential of cannabinoid and angiotensin receptors as targets in the therapy of Parkinson's disease (PD). While endocannabinoids are neuromodulators that act through the CB and CB cannabinoid receptors, the renin angiotensin-system is relevant for regulation of the correct functioning of several brain circuits. Resonance energy transfer assays in a heterologous system showed that the CB receptor (CBR) can directly interact with the angiotensin AT receptor (ATR). Coactivation of the two receptors results in increased G-signaling. The AT-CB receptor heteromer imprint consists of a blockade of ATR-mediated signaling by rimonabant, a CBR antagonist. Interestingly, the heteromer imprint, discovered in the heterologous system, was also found in primary striatal neurons thus demonstrating the expression of the heteromer in these cells. In situ proximity ligation assays confirmed the occurrence of AT-CB receptor heteromers in striatal neurons. In addition, increased expression of the AT-CB receptor heteromeric complexes was detected in the striatum of a rodent PD model consisting of rats hemilesioned using 6-hydroxydopamine. Expression of the heteromer was upregulated in the striatum of lesioned animals and, also, of lesioned animals that upon levodopa treatment became dyskinetic. In contrast, there was no upregulation in the striatum of lesioned rats that did not become dyskinetic upon chronic levodopa treatment. The results suggest that therapeutic developments focused on the CBR should consider that this receptor can interact with the ATR, which in the CNS is involved in mechanisms related to addictive behaviors and to neurodegenerative and neuroinflammatory diseases.