Cys-loop receptors on cannabinoids: All high?

Abstract

Endocannabinoids (eCBS) are endogenously derived lipid signaling molecules that serve as tissue hormones and interact with multiple targets, mostly within the endocannabinoid system (ECS). The ECS is a highly conserved regulatory system involved in homeostatic regulation, organ formation, and immunomodulation of chordates. The term “cannabinoid” evolved from the distinctive class of plant compounds found in Cannabis sativa, an ancient herb, due to their action on CB1 and CB2 receptors. CB1/2 receptors are the primary targets for eCBs, but their effects are not limited to the ECS. Due to the high interest and extensive research on the ECS, knowledge on its constituents and physiological role is substantial and still growing. Crosstalk and multiple targeting of molecules are common features of endogenous and plant compounds. Cannabimimetic molecules can be divided according to their origin, natural or synthetic, including phytocannabinoids (pCB’s) or synthetic cannabinoids (sCB’s). The endocannabinoid system (ECS) consists of receptors, transporters, enzymes, and signaling molecules. In this review, we focus on the effects of cannabinoids on Cys-loop receptors. Cys-loop receptors belong to the class of membrane-bound pentameric ligand gated ion channels, each family comprising multiple subunits. Mammalians possess GABA type A receptors (GABAAR), glycine receptors (GlyR), serotonin receptors type 3 (5-HT3R), and nicotinic acetylcholine receptors (nAChR). Several studies have shown different modulatory effects of CBs on multiple members of the Cys-loop receptor family. We highlight the existing knowledge, especially on subunits and protein domains with conserved binding sites for CBs and their possible pharmacological and physiological role in epilepsy and in chronic pain. We further discuss the potential for cannabinoids as first line treatments in epilepsy, chronic pain and other neuropsychiatric conditions, indicated by their polypharmacology and therapeutic profile.

The Polypharmacological Effects of Cannabidiol

“…Both excitatory and inhibitory synaptic transmission can be modulated by these receptors [ 66 ]. In humans, a reduction in α7-nAChR expression has been associated with an increase in seizure susceptibility [ 67 ]. α7-nAChR agonists have pro-cognitive effects, and its modulation has been proposed to be relevant for the treatment of Alzheimer’s disease (AD) or cognitive symptoms of schizophrenia, among others [ 68 ].…”

Ethnobotanical and Ethnopharmacological Surveys of Cannabis sativa (Beldiya Species) Use in the Provinces of Taounate and Al Hoceïma

“…The high concentration of cannabinoids in the flowers explains their preference, as these compounds modulate the body's homeostasis and mood by interacting with the peripheral and central nervous systems, especially with the cannabinoid-1 and cannabinoid-2 (CB1 and CB2) receptors. [33][34][35][36][37] However, some studies indicated different preferences for other plant parts. For example, Lozano et al reported a significant inclination toward the seeds, which are rich in essential fatty acids and proteins.…”

Structural Basis for Molecular Recognition of Cannabinoids by Inhibitory Cys-Loop Channels

“…Virtually all inhibitory functions within the CNS involve GlyRs and GABA A Rs; thus, cannabinoids’ ability to modulate these channels confers them enormous pharmacological potential and offers new therapeutic opportunities. Recently, Schmiedhofer et al conducted a comprehensive review on endo- and phytocannabinoids’ effects on cationic and anionic channels, including pharmacological aspects, and discussed cannabinoids’ possible impact as first-line treatments for epilepsy, chronic pain, and other neuropsychiatric disorders . Here, we review the advances made toward understanding the molecular determinants of cannabinoid action, starting with the first reports of phytocannabinoids’ effects on inhibitory Cys-loop channels, the establishment of their significance in THC-induced analgesia, followed by a critical revision of the different molecular models proposed over the years.…”

“…Recently, Schmiedhofer et al conducted a comprehensive review on endo-and phytocannabinoids' effects on cationic and anionic channels, including pharmacological aspects, and discussed cannabinoids' possible impact as first-line treatments for epilepsy, chronic pain, and other neuropsychiatric disorders. 31 Here, we review the advances made toward understanding the molecular determinants of cannabinoid action, starting with the first reports of phytocannabinoids' effects on inhibitory Cys-loop channels, the establishment of their significance in THC-induced analgesia, followed by a critical revision of the different molecular models proposed over the years. To conclude, we examine recent findings obtained from both the resolution of cryo-EM structures 32 and thorough computational studies on the cannabinoid binding mode, 33 comparing results, strengths, and limitations of each method.…”