Cannabinoid receptor 1 modulates the autophagic flux in a non-canonic fashion

Cannabinoid Receptor 1 (CBR1) has been initially described as the receptor for Δ9-THC in the central nervous system (CNS), mediating retrograde synaptic signaling exerted by the endocannabinoid system. CBR1 is expressed in different CNS regions, but is also present in a variety of peripheral tissues, where one well described function of CBR1 there is the direct modulation of the energy homeostasis of the cell. A main constituent contributing to the regulation of the intracellular energy status is the evolutionary conserved autophagic machinery, which is in addition an important cellular degradation pathway and thereby a regulator for protein homeostasis. This prompted us to examine the role of CBR1 in the control of autophagic activity in mammalian cells. Manipulating CBR1 activity caused an elevated autophagic flux, while the expression of autophagy-related genes remained unaltered. This effect was independent of mTORC1, known as major switch in the control of canonical autophagy. In addition, knocking down key-components of the BECLIN1-complex, which is the second canonical autophagy control complex, is not sufficient to reduce the CBR1 dependent modulation of the autophagic flux. Therefore, CBR1 activity seems to affect the autophagic flux in a non-canonic fashion and might be a pharamacological target for clinical use to modulate the autophagic activity as a novel treatment strategy for pathological states, which are linked to a disturbed autophagic function.

This study was supported by DFG FOR-926, Corona-Stiftung