Figure 6

Schematic representation of hypothesized interactions between Smoothened and the CB1 receptor in the embryo. Left panel. During typical development, Sonic Hedgehog (Shh) alleviates the repression of Smoothened (Smo) by Patched (Ptch1) which allows Smo to translocate to the primary cilium. In the primary cilium, Smo, a G-protein coupled receptor, activates Shh pathway signaling, partly through its association with Gαi proteins. Gαi inhibits adenyl cyclase (AC) which, by inhibiting the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP), inhibits the accumulation of protein kinase A (PKA) and prevents the proteolytic processing of Gli transcription factors into their repressor forms (Gli R). By maintaining the Gli activator (Gli A) state, the inhibition of PKA facilitates the gene transcription necessary for normal cell proliferation and development. Right panel. Alcohol (EtOH) and cannabinoids converge onto the Shh pathway to alter typical development. A mechanism by which alcohol affects development is through its inhibition of Shh, which reduces the number of Smo molecules at the primary cilia, and thereby reduces the activation of Shh signaling cascades. Cannabinoids, on the other hand, have two mechanisms of action. First, cannabinoids directly inhibit Smo and prevent the signaling of Smo through Gαi proteins, as described above. Additionally, cannabinoids stimulate CB1 receptors that, in the primary cilia, form heterodimers with Smo. CB1-Smo heterodimers associate with Gαs proteins, in addition to Gαi proteins. When Gαs signaling is activated by CB1 receptor agonism, PKA is stimulated which increases Gli R and decreases Gli A. Co-exposure to alcohol and cannabinoids therefore, inhibits Shh and Smo-Gαi signaling, while simultaneously stimulating CB1-Gαs signaling, and ultimately causing a greater reduction in Shh pathway activation than does exposure to either drug alone.