Interactions between the Nicotinic and Endocannabinoid Receptors at the Plasma Membrane

Abstract

Compartmentalization, together with transbilayer and lateral asymmetries, provide the structural foundation for functional specializations at the cell surface, including the active role of the lipid microenvironment in the modulation of membrane-bound proteins. The chemical synapse, the site where neurotransmitter-coded signals are decoded by neurotransmitter receptors, adds another layer of complexity to the plasma membrane architectural intricacy, mainly due to the need to accommodate a sizeable number of molecules in a minute subcellular compartment with dimensions barely reaching the micrometer. In this review, we discuss how nature has developed suitable adjustments to accommodate different types of membrane-bound receptors and scaffolding proteins via membrane microdomains, and how this "effort-sharing" mechanism has evolved to optimize crosstalk, separation, or coupling, where/when appropriate. We focus on a fast ligand-gated neurotransmitter receptor, the nicotinic acetylcholine receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as a paradigmatic example.

Keywords: acetylcholine receptor; cannabinoid receptor; cannabinoids; membrane domains; nanodomains; neurotransmitter receptors; plasma membrane.

Figure 1

Schematic illustration of the biosynthetic pathway followed by ECs N-acylethanolamine (AN) and 2-arachidonoylglycerol (2-AG) by NAPE-PLD and DAG lipase, respectively. Both AN and 2-AG bind to presynaptic CB1Rs expressed on GABAergic, glutamatergic and cholinergic terminals, precluding neurotransmitter release. Induction of DOPA secretion by primary inhibition of GABA release is involved in the reward pathway in the brain. Abbreviations: PLD, N-acyl phosphatidylethanolamine phospholipase D; DAG, diacylglycerol; NAT, N-acyltransferase; PE, Phosphatidylethanolamine; nAChRs, nicotinic acetylcholine receptors; CB1R, cannabinoid type 1 receptor; AMPA, amino-3-hydroxy-5-methyl-4-isoazolepropionate receptor; GABA, γ-aminobutyric acid; GABAR, GABA receptor; NMDAR, N-methyl-D-aspartate receptor; DOPA, dopamine; DOPAR, DOPA receptor; VTA, ventral tegmental area; NAc, nucleus accumbens.

Figure 2

Schematic depiction of the interactions between cannabinoid receptor signaling and lipid domains. Neuromodulation upon agonist binding to CB1Rs and CB2Rs (unphosphorylated receptors) induces Gi/o-dependent inhibition of adenylyl cyclase (AC) activity and activation of different MAPK cascades. CB1R positively regulates inwardly rectifying K⁺ channels, whereas it negatively regulates voltage-gated Ca²⁺ channels. In addition, the CB1R can activate PLC at the plasma membrane and can also signal through non-G proteins such as the adaptor protein FAN. The phosphorylated CB1R is a target of β-arrestin. The attenuation of CB1R signaling at cholesterol-rich lipid domains occurs through a Rab5-dependent endocytic mechanism. Once internalized, the CB1R may either be recycled back to the plasma membrane through a Rab4-dependent mechanism or further targeted to lysosomal degradation. The CB2R does not reside in or interact with Lo lipid platforms. Alteration of ordered lipid domain integrity either by depleting or supplying cholesterol is shown to inhibit or enhance the internalization of CB1R, respectively. The inset depicts a closer view of the cholesterol-rich Lo lipid domain (marked with a dotted line in the main figure). Cholesterol molecule in gray, sphingolipids in red and other phospholipids in yellow.