The study investigates the orphan receptor GPR55, which is a novel cannabinoid receptor. The researchers used cells transfected with human cDNA for GPR55 to test their ability to bind and mediate GTPγS binding by cannabinoid ligands. They found that GPR55 binds to and is activated by the cannabinoid ligand CP55940, and that endocannabinoids such as anandamide and virodhamine also activate GTPγS binding via GPR55. Ligands like cannabidiol and abnormal cannabidiol, which do not exhibit CB1 or CB2 activity, also showed activity at GPR55. GPR55 couples to Gα13 and can mediate activation of rhoA, cdc42, and rac1. These findings suggest that GPR55 is a novel cannabinoid receptor with a unique ligand profile compared to CB1 and CB2, which will help in understanding its physiological functions.The study investigates the orphan receptor GPR55, which is a novel cannabinoid receptor. The researchers used cells transfected with human cDNA for GPR55 to test their ability to bind and mediate GTPγS binding by cannabinoid ligands. They found that GPR55 binds to and is activated by the cannabinoid ligand CP55940, and that endocannabinoids such as anandamide and virodhamine also activate GTPγS binding via GPR55. Ligands like cannabidiol and abnormal cannabidiol, which do not exhibit CB1 or CB2 activity, also showed activity at GPR55. GPR55 couples to Gα13 and can mediate activation of rhoA, cdc42, and rac1. These findings suggest that GPR55 is a novel cannabinoid receptor with a unique ligand profile compared to CB1 and CB2, which will help in understanding its physiological functions.