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Understanding Cannabinoid Receptors: Structure and Function

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Understanding Cannabinoid Receptors: Structure and Function Folia Biologica et Oecologica 14: 1–13 (2018) Acta Universitatis Lodziensis Understanding cannabinoid receptors: structure and function ANGELIKA ANDRZEJEWSKA1, KLAUDIA STASZAK1, MARTA KACZMAREK-RYŚ1, RYSZARD SŁOMSKI1,2, SZYMON HRYHOROWICZ*1 1Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479 Poznan, Poland 2Department of Biochemistry and Biotechnology, University of Life Sciences, Dojazd 11, 60-632 Poznan, Poland E-mail: [email protected] ABSTRACT The endocannabinoid system (ECS) consists of the endocannabinoids, cannabinoid receptors and the enzymes that synthesize and degrade endocannabinoids. The whole EC system plays an important role in the proper functioning of the central and autonomic nervous system. ECS is involved in the regulation of the body energy and in the functioning of the endocrine system. It can affect on the regulation of emotional states, motoric movement, operations of the endocrine, immune and digestive system. Many of the effects of cannabinoids are mediated by G coupled –protein receptors: CB1, CB2 and GPR55 but also of transient receptor potential channels (TRPs) which not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides. In this review work we briefly summarize the role and action of cannabinoid receptors CB1 and CB2, protein-coupled receptor 55 (GPR55) and transient receptor potential vanilloid 1 (TRPV1). K EY WORDS: cannabinoid receptors, CB1, CB2, TRPV1, GPR55 Introduction Cannabinoid receptors are one of the consisting of lipophilic substances most abundant neuronal receptors that are stimulating their function – linked through G proteins (the guanine- endocannabinoids and exogenous nucleotide-binding proteins) to the agonists, as well as enzymes governing effectors system (called G-protein the synthesis and degradation (Pawlak et coupled receptors, GPCRs). This group al., 2011). In recent years, researches have includes two well characterized types of provided evidence that the system is more receptors – CB1 and CB2. They are part complicated and additional receptor types of the endocannabinoid system (ECS), should exist to explain ligand activity in DOI: 10.1515/fobio-2017-0004 FOLIA BIOLOGICA ET OECOLOGICA many physiological processes. To date ECS is involved in the regulation of the other types of cannabinoid receptors, non- body energy and in the functioning of the CB1 and non- CB2, have been reported endocrine system. It can affects on the such as orphan GPR55 and TRPV1 regulation of emotional states, motoric receptors, which could explain not movement, operations of the endocrine, completely understood pathway system immune and digestive system (Bisogno et al., 2001; Ryberg et al., 2007; (Komorowski and Stępień, 2007). This Befort, 2015). system plays a major role in the control of It is known that mammalian tissues pain, in reward processing and in the may produce endogenous ligands of development of addiction (Befort, 2015). cannabinoid receptors. First discovered Although the relationship between the substance of this type was the amide activity of cannabinoid receptors and cell derivative of arachidonic acid - proliferation is not fully understood. It is arachidonoyl ethanolamide - AEA, which known that certain agonists of these was called anandamide. Later was receptors, including anandamide, inhibit discovered another endocannabinoid of proliferation of cultured human breast lipid structure - 2-arachidonyl glycerol (2- cancer cells. It is worth noting, that the AG). These substances can activate tests on the effectiveness of cannabinoids receptors and are synthesized on demand in the treatment of neurodegenerative in response to elevations of intracellular diseases (such as Parkinson disease) are calcium. Studies show that repeated carried out, because of their administration of cannabinoid receptor neuroprotective properties (Konarska and agonists may cause the development of Ellert, 2004). tolerance to some of their effects (Pertwee, 2006; Pertwee, 2009). Methods Exogenous cannabinoids has been Publication search was performed in termed substances that are extracted from Medline and PubMed database. The key the marijuana plant Cannabis sativa or are words used were cannabinoids receptors, synthesized artificially. The most popular cannabinoids, CB1, CB2, GPR55, examples of these substances are TRPV1. We decided to use both, the older cannabinol (CBN), cannabidiol (CBD) papers describing the discovery of and delta-9-tetrahydrocannabinol (Δ9- cannabinoid receptors and more recent THC). The last of them is the major publications, describing possible new immunomodulatory and psychoactive interactions between potential novel component of the marijuana (Cabral and receptors and cannabinoids. Griffin-Thomas, 2009). The discovery of CB1 and CB2 Cannabinoid receptor type 1 - CB1 receptors was followed by the receptor development of CB1- and CB2-selective CB1 and CB2 receptors belong to G- cannabinoid receptor antagonists. These protein coupled receptor (GPCR) family. substances block the normal operation of The cannabinoid receptor type 1 is the receptor and may weaken or suppress primarily located in central and peripheral agonist (Pertwee, 2006). nervous system. The CB1 receptors The whole endocannabinoid system expressed predominantly in the brain. The plays an important role in the proper highest density of cannabinoids binding functioning of the central and autonomic sites are in first and fourth layer of the nervous system. The reason for such cerebral cortex, hypothalamus, pyramidal action of cannabinoids is their easy cell layer of the hippocampus, passage through the blood-brain barrier. pariaqueductal gray dorsal horn and in the 2 ANDRZEJEWSKA A. ET AL. FOLIA BIOLOGICA ET OECOLOGICA limbic system. These areas associated the et al., 2011). For the first time the endocannabinoid system with memory complementary DNA of this receptor was processes, modulation of emotional states isolated from a cDNA library of rat and mobility, as well as anticonvulsant cerebral cortex in 1990 (Konarska and properties of cannabinoids. CB1 receptors Ellert, 2004; GeneCards). In 1995, Shire are also observed in basal ganglia and and his team have isolated a shorter cerebellum but in lower density than for isoform of the receptor - composed of 411 example in rodents. Lower density of CB1 amino acids, as a result of deletion of 167 is also observed in the structure of the base pairs in the nucleotide sequence. This vental tegmental area and nucleus change resulting protein product, a variant accumbens, which is responsible for the CB1A, has a molecular weight of 46 kDa development of happiness and reward (Shire et al., 1995). In 2004, Ryberg et al. feelings, also known as reward system identified a second isoform of the receptor (Komorowski and Stępień, 2007). CB1 - a variant CB1B - with a molecular Initially it was believed that these weight of 49 kDa, constructed of 439 receptors are present only in the brain, but amino acids. Both variants have altered their presence in peripheral locations was the ability of the ligand binding and also demonstrated. CB1 receptors were activation as compared to the original observed in inter alia in the pituitary length transcript (Ryberg et al., 2005). gland, immune cells, tissues, digestive The construction of CB1 receptors is tract, reproductive system, heart, lung, well characterized, comprising a single, intestine, tonsil, thymus, spleen and highly fold to polypeptide chain. Chain placenta (Rutkowska and Jamontt, 2005; completes its structure through the cell Ryberg et al., 2007; Busquets-Garcia et membrane seven times to form seven al., 2016). hydrophobic transmembrane domains The cannabinoid receptor type 1 is the (TM I - TM VII) (Kazula, 2009). Figure 1 product of CNR1 gene expression. shows a general scheme for the Medium sized protein is 52 858 Da and it construction of CB1 receptor in human. is composed of 472 amino acids (Pawlak Figure 1. Construction of cannabinoid receptor type 1 (CB1). The numbers at the beginning (1) and end (472) of the chain indicate the direction of numbers of amino acids. Terminal residues, amino (N-) and carboxy (C- ), transmembrane domains (TM I-VII), intracellular (ic) and extracellular (ec) loops are also marked. Polypeptide chain ends of the receptor, membrane. The N-terminus is located are located on different side of the cell outside the cell and the C-terminus have UNDERSTANDING CANNABINOID RECEPTORS: ACTION AND FUNCTION 3 FOLIA BIOLOGICA ET OECOLOGICA an intracellular localization – in the and rat, the similarity is equal respectively cytoplasm. In addition, the receptor has in to 93% and 97% (Konarska and Ellert, its structure a three extracellular and three 2004; Kazula, 2009). intracellular loops. The second The primary activity of cannabinoid extracellular loop and the third receptors is the regulation of the transmembrane domain may bind CB1 permeability of adjacent ion channels. agonists, while the third loop, which is This is done through interaction with the located inside the cell, binds the inhibitory trimeric protein Gi/Go, which act as protein G. Construction of receptor shows adapter proteins. General scheme of a significant interspecies preservation. functioning CB1 receptor is shown in Comparing the nucleotide and amino acid Figure 2. structures of the CB1 receptor in human Figure 2. Diagram of the mechanism of signal transduction by the CB1 receptor in presynaptic bulb (based on Ameri, 1999
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