Cell-autonomous endocannabinoid production shapes polarized and dynamic distribution and signaling patterns of cannabinoid CB1 receptors in neurons

Abstract

Interaction with the highly regulated local lipid environment is emerging as key dynamic component of cellular function through the control of the structure, conformation, and function of cell-membrane-embedded proteins, such as G-protein-coupled receptors (GPCRs). The type-1 cannabinoid receptor CB1, because of a relatively unstable GPCR structure and specific entry sites for lipids diffusing from the plasma membrane, may be particularly sensitive to such effects. In this chapter, we will discuss the first level of this lipid-protein interaction: the cellautonomous scale, the foundation on which other important layers, such as paracrine or transsynaptic signaling systems, are built in vivo. Recent studies reveal an intricate balance between the polarized production of endocannabinoid (eCB) lipids and the polarized targeting and signaling of CB1. The endocannabinoid 2-arachidonoylglycerol (2-AG), which is specifically produced in the somatodendritic plasma membrane, exerts cell-autonomous tonic activation on somatodendritic CB1 receptors. This activation, in addition to important local signaling effects, also regulates CB1 responses to other cannabinoids and provides the driving force for important basal endocytosis, which is followed by transcytotic CB1 delivery to the axonal plasma membrane, where the large majority of CB1Rs accumulate at steady state. This cell-autonomous tonic CB1 activation is based on two important properties of the endocannabinoid system: the elevated basal production of eCBs in specific regions of the plasma membrane (i.e., basal activation) and the structural instability of the CB1 protein (i.e., constitutive activity). Key elements of this unusually dynamic functional model are valuable to better understand activation mechanisms of presynaptic CB1 receptors and may also explain the high diversity of reported CB1 ligands, ranging from peptide and lipid allo- and orthosteric regulators to the phytocannabinoid Δ9-THC, the psychoactive component of marijuana.