Figure 2.

Examples of the context-dependent complexity of the cannabinoid signaling. (a) Overview of the most important potential targets of the phytocannabinoids (pCBs), which can be concentration-dependently activated/antagonized/inhibited by these molecules. Each pCB can be characterized by a unique molecular fingerprint, and every pCB was found to interact with only a subset of potential targets shown on panel (a). Importantly, the interactions can even result in opposing outcomes (e.g., THC is a partial CB₁ agonist, whereas CBD is a CB₁ antagonist/inverse agonist), making prediction of cellular effects of the pCBs even more difficult. (b) The actual biological response, which develops following the activation of CB₁ receptor depends on several additional factors, including biased agonism [31,32,65,66,67,68,69,70,71,72,73], possible receptor heteromerization [32,74,75,76,77,78,79,80], localization (i.e., cell membrane vs. mitochondria vs. lysosomes [81,82,83]), as well as the composition of the lipid microenvironment of the given membrane [58,84]. Green arrows on panel (b): the most common signaling pathways of CB₁. Note that besides CB₁, biased agonism is well-described in case of CB₂, GPR18, GPR55 and GPR119 as well, whereas CB₂ was proven to heteromerize with, e.g., C-X-C chemokine receptor type 4 chemokine receptor (CXCR4), or GPR55 (for details, see the above references). The question mark indicates that functional heteromerization of CB₁ and GABA_B receptors is questionable. AT₁: angiotensin II receptor type 1; CYP: cytochrome P450 enzymes; D₂: dopamine receptor 2; EMT(s): endocannabinoid membrane transporter(s); ENT1: equilibrative nucleoside transporter 1; GABA_B: γ-aminobutyric acid receptor B; LPA₁: lysophosphatidic acid receptor 1; Na_v: voltage-gated Na⁺ channels; OX₁: orexin 1 receptor; VDAC1: voltage-dependent anion channel 1. The figure was adapted and modified from [31] originally licensed under CC-BY, version 4.0.