Good news for CB 1 receptors: endogenous agonists are in the right place

Endocannabinoids are endogenous ligands of brain‐type (CB 1 ) and spleen‐type (CB 2 ) cannabinoid receptors. N ‐Arachidonoylethanolamine (anandamide, AEA) and 2‐arachidonoylglycerol (2‐AG) are prototype members of the fatty acid amides and the monoacylglycerols, two groups of endocannabinoids. Unlike CB 1 , CB 2 receptors do not reside within ‘caveolae’, specialized membrane microdomains that are well‐known modulators of the activity of a number of G protein‐coupled receptors. In this issue of the British Journal of Pharmacology , Rimmerman and coworkers demonstrate that 2‐AG is entirely localized in the caveolae of dorsal root ganglion cells, where also part of AEA (∼30%) can be detected. However, most of AEA (∼70%) was detected in non‐caveolae fractions, that is where CB 2 receptors are localized. The different interaction of AEA and 2‐AG with membrane microdomains might have significant implications for endocannabinoid‐dependent autocrine and/or retrograde‐paracrine signalling pathways. It also raises an important question about the structural determinants responsible for a different localization of two apparently similar endocannabinoids within lipid bilayers. British Journal of Pharmacology (2008) 153 , 179–181; doi: 10.1038/sj.bjp.0707566 ; published online 12 November 2007