The ECS is composed of two major G-protein couple receptors named cannabinoid receptor type-1 (CB1) and type-2 (CB2), a class of endogenous signaling lipids (endocannabinoids) and a series of enzymes involved in their biosynthesis and degradation.

The two most abundant and well-studied endocannabinoids are anandamide (AEA) and 2-arachidonoyl glycerol (2-AG). At the synaptic level, upon the arrival of an action potential, neurotransmitters are released from presynaptic neurons into the synaptic cleft.

Increase of intracellular Ca2+ concentration in the postsynaptic neurons activates the biosynthetic enzymes for AEA and 2-AG, which are released in the synaptic cleft. Endocannabinoids activate CB1 receptors expressed on pre-synaptic neurons blocking the release of further neurotransmitters (negative feedback, retrograde signaling). Finally, endocannabinoids are transported intracellularly where they are degraded by specific enzymes.

 

Although data from independent laboratories have clearly suggested the existence of an endocannabinoid membrane transport mechanism (reviewed in Nicolussi & Gertsch, 2015), this has remained elusive for many years.

Thanks to the prolonged support of NCCR TransCure and other founding agencies, recently the research group of Prof. Jürg Gertsch at the University of Bern was successful to identify the molecular entities responsible for endocannabinoid transport across cell membranes (not yet published) and first-in-class selective endocannabinoid reuptake inhibitors (SERIs).

First generation SERIs have been instrumental to uncover a new pharmacological modulation of the endocannabinoid system resulting from the inhibition of endocannabinoid cell reuptake (Chicca et al., PNAS 2017; Reynoso-Moreno et al., 2018).

SERIs’ mechanism of action enables restoration of the full spectrum of endocannabinoid biological activities.