The Synthetic Cannabinoid WIN55,212-2 Can Disrupt the Golgi Apparatus Independent of Cannabinoid Receptor-1

Abstract

The synthetic cannabinoid WIN55,212-2 (WIN) is widely used as a pharmacological tool to study the biologic activity of cannabinoid receptors. In contrast to many other cannabinoid agonists, however, WIN also causes broad effects outside of neurons, such as reducing inflammatory responses, causing cell cycle arrest, and reducing general protein expression. How exactly WIN causes these broad effects is not known. Here we show that WIN partially disrupts the Golgi apparatus at nanomolar concentrations and fully disperses the Golgi apparatus in neuronal and non-neuronal cells at micromolar concentrations. WIN55,212-3, the enantiomer of WIN; JWH-018, a related alkylindole; or 2-arachidonoylglycerol, an endocannabinoid, did not cause Golgi disruption, suggesting that the effect was specific to the chirality of WIN. WIN treatment also perturbed the microtubule network. Importantly, WIN disrupted the Golgi in primary cortical neurons derived from mice where cannabinoid receptor-1 (CB1) was genetically knocked out, indicating that the effects were independent of CB1 signaling. The Golgi dispersion could not be explained by WIN's action on peroxisome proliferator-activated receptors. Our results show that WIN can disrupt the Golgi apparatus independent of CB1 in cultured cells. These effects could contribute to the unique physiologic effects that WIN exhibits in neuronal behavior, as well as its role as an antiproliferative and anti-inflammatory agent. SIGNIFICANCE STATEMENT: The synthetic cannabinoid WIN55,212-2 (WIN), widely used to investigate the cannabinoid system, also shows unique broader effects at cellular and organismal levels compared to endogenous cannabinoids. Our study shows that WIN can disrupt the Golgi apparatus and the microtubule network in multiple cell types, independent of cannabinoid receptors. These results could explain how WIN reduces surface levels of proteins and contributes to the unique physiological effects observed with WIN.