New Insights Into Peptide Cannabinoids: Structure, Biosynthesis and Signaling

Abstract

Classically, the endocannabinoid system (ECS) consists of endogenous lipids, of which the best known are anandamide (AEA) and 2 arachidonoylglycerol (2-AG), their enzyme machinery for synthesis and degradation and their specific receptors, cannabinoid receptor one (CB1) and cannabinoid receptor two (CB2). However, endocannabinoids also bind to other groups of receptors. Furthermore, another group of lipids are considered to be endocannabinoids, such as the fatty acid ethanolamides, the fatty acid primary amides and the monoacylglycerol related molecules. Recently, it has been shown that the hemopressin peptide family, derived from α and β chains of hemoglobins, is a new family of cannabinoids. Some studies indicate that hemopressin peptides are expressed in the central nervous system and peripheral tissues and act as ligands of these receptors, thus suggesting that they play a physiological role. In this review, we examine new evidence on lipid endocannabinoids, cannabinoid receptors and the modulation of their signaling pathways. We focus our discussion on the current knowledge of the pharmacological effects, the biosynthesis of the peptide cannabinoids and the new insights on the activation and modulation of cannabinoid receptors by these peptides. The novel peptide compounds derived from hemoglobin chains and their non-classical activation of cannabinoid receptors are only starting to be uncovered. It will be exciting to follow the ensuing discoveries, not only in reference to what is already known of the classical lipid endocannabinoids revealing more complex aspects of endocannabinoid system, but also as to its possibilities as a future therapeutic tool.

The Role of Cannabinoids in CNS Development: Focus on Proliferation and Cell Death

“…RVD hemopressin, an N-terminally extended form of hemopressin, acts as a negative allosteric modulator of CB1R; however, it is a positive allosteric modulator of CB2R. In addition to modulating classical cannabinoid receptors, it has been described that hemopressins can modulate other receptors and components of the endocannabinoid system (Riquelme-Sandoval et al 2020).…”

Cannabinoids: an Effective Treatment for Chemotherapy-Induced Peripheral Neurotoxicity?

“…More recently, another group of lipids are considered to be endocannabinoids, including the fatty acid ethanolamides, the fatty acid primary amides and the monoacylglycerol-related molecules. Finally, it has been shown that the hemopressin peptide family, derived from α and β chains of hemoglobins, is likely to be a new family of cannabinoids [11]. The endocannabinoid system is highly integrated in the nervous system circuitry and it influences, and is influenced by, many other signaling pathways.…”

“…Cannabidiol (CBD) is another constituent of cannabis, present at variable levels, which interacts with the endocannabinoid system as well as other neuromodulatory systems. Although several non-canonical cannabinoid receptors have been described [11], CB1 cannabinoid receptors (CB1R) and CB2 cannabinoid receptors (CB2R) are the best-characterized cannabinoid receptors. Both are G protein-coupled receptors able to inhibit adenylyl cyclase and certain voltage-sensitive calcium channels, to stimulate mitogen-activated protein (MAP) kinases, and recruit beta-arrestins, among other actions [12,13].…”

“…By contrast, although they have a neuronal expression [20], CB2R are primarily expressed in cells of immune origin [21,22], including microglia [20,23], but also in pancreatic acinar cells, adipocytes, skeletal muscle cells, cardiomyocytes, and endothelial cells [15]. CB2R are also expressed in astrocytes, oligodendrocytes, neural stem/progenitor cells, vascular elements in the brain [11], and are upregulated in the CNS and dorsal root ganglia (DRG) by pathological pain states [24].…”

The cannabinoid receptors system in horses: Tissue distribution and cellular identification in skin

“… 7 The CBRs activation and signal transduction pathways are initiated after binding of 3 general ligand subtypes. 8 First, naturally‐synthesized endocannabinoids are represented by anandamide (N‐arachidonoylethanolamine) and 2‐arachidonoylglycerol (2‐AG), which bind classical CBRs. In turn, another endogenous ligand, palmitoylethanolamide (PEA), has an affinity to non‐CBRs restricted to peroxisome proliferator‐activated receptor alpha (PPAR‐α).…”