Beside their actions through the CB1 and CB2 receptors, the endocannabinoids, as well as the exogenous cannabinoids, bind also to other receptors [15]. Among these are the transient receptor potential vanilloid 1 (TRPV1) cation channel, peroxisome proliferator-activated receptors (PPARs, [19]), and at least three orphan GPCRs: GPR55, that we have cloned [20] and which has been reported as a cannabinoid receptor [21]; GPR18; and GPR119 [22,23,24]. It is also important to note that many receptor heteromeric complexes have been established in vitro and in vivo, as reviewed in [24,25], such as the CB1R–CB2R heteromers [26], and between CB1R or CB2R and a large variety of other receptors. Notable are the CB1R heteromers with dopamine D2 receptor [27,28], serotonin receptors 5HT1A [29] and 5HT2A [30], adenosine receptor A2A [31], and GPR55 [32]. All of this diversification of signaling through the cannabinoid receptors and the range of heteromers may explain the varied involvement of the cannabinoid system in many pathophysiologic conditions and may be responsible for the variance in response to endogenous and exogenous agonists and pharmacological modulators of the cannabinoid system.
