Targeting and identification of the endocannabinoid transporter
Endocannabinoids are important physiological modulators of major neurotransmitters in the CNS and immune and metabolic processes. Once generated at the inner leaflet of the cell membrane they efflux and interact with cannabinoid receptors. Receptor engagement is terminated by cellular uptake and enzymatic degradation. Current data strongly indicate that endocannabinoids, which are arachidonic acid-derived lipids, do not cross cell membranes by “passive diffusion” but use a facilitated process that can be inhibited by selective molecular probes. The Gertsch group believes that endocannabinoid membrane transport is mediated by a putative membrane protein which they want to identify. They showed that endocannabinoid transport is bidirectional and not mediated via the known cytoplasmic binding proteins (Chicca et al., J Biol Chem, 287, 34660-82, 2012). Currently, large efforts are ongoing in collaboration with chemists within TransCure (groups Reymond and Altmann) to synthesize highly specific and affine endocannabinoid uptake inhibitors. Most promising leads are being evaluated in vivo in mice. Data suggest that endocannabinoid reuptake inhibition provides a feasible therapeutic strategy to potentiate endocannabinoid signaling during pathological conditions such as psychiatric disorders or inflammatory pain. In addition, highly potent and selective inhibitors serve as tool compounds to identify the putative endocannabinoid transporter in addition to the genetic approaches.
University of Bern, Institute of Biochemistry and Molecular Medicine
|Nicolussi Simon (Ph.D. Student)
Gertsch Jürg (PI)
Chicca Andrea (Postdoctoral Fellow)
Gachet Otañez Salomé (Postdoctoral Fellow / Marie Curie Fellow)