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Understanding Cannabinoid Receptors: Structure and Function

Understanding Cannabinoid Receptors: Structure and Function

Folia Biologica et Oecologica 14: 1–13 (2018)

Acta Universitatis Lodziensis

Understanding 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 that synthesize and degrade endocannabinoids. The whole EC system plays an important role in the proper functioning of the central and . 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 are mediated by G coupled –protein receptors: CB1, CB2 and GPR55 but also of transient potential channels (TRPs) which not only induce the sensation of 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 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 - proliferation is not fully understood. It is arachidonoyl ethanolamide - AEA, which known that certain agonists of these was called . Later was receptors, including anandamide, inhibit discovered another endocannabinoid of proliferation of cultured human breast 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 . Studies show that repeated carried out, because of their administration of 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 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 (CBN), (CBD) papers describing the discovery of and delta-9- (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 . 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 , 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 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 and and his team have isolated a shorter 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 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 and Konarska, Ellert, 2004).

Start of the signalling reaction is the start of multiple MAP kinase cascades conditioned by the appearance of the (mitogen-activated protein kinase), which appropriate agonist (e.g. THC) or by an play a role i.e.: in gene expression, endogenous ligand (e.g. anandamide and division, differentiation and apoptosis of 2-arachidonoylglycerol) which binds to cells. Cascade of reactions is responsible the receptor directly (Nicoll et al., 2012). for inhibition of (AC) When the ligand join the outer loop of activity, which reduces the amount of the receptor, located in the presynaptic cyclic AMP (Cyclic 3 ', 5'- membrane, following its stimulation by monophosphate, cAMP), or intracellular changes the conformation of the internal relay II row. This can lead to a reduction receptor. The result is a Gi/Go protein of protein kinases (PKA), which are attachment to the inner loop of the CB1 responsible for phosphorylation of the receptor, which then, due to the exchange KA (depending on of guanosine 5'-diphosphate (GDP) by voltage) causing a greater flow of these guanosine 5'-triphosphate (GTP) ions. Activation of G-proteins, by CB1 dissociate an active subunits α, β and γ. receptors, directly produces inhibition of The result of the G proteins activation is calcium channels, and activation of

4 ANDRZEJEWSKA A. ET AL. FOLIA BIOLOGICA ET OECOLOGICA potassium channels Kir and thus receptors in the retina of adult rats and transporting accordance with the other , and in mouse brain and electrochemical gradient. As a result the peripheral nerves of mice and guinea pigs. above signal cascade, occurs to a reduced (Rutkowska and Jamontt, 2005). release of neurotransmitters from Studies suggest that these receptor is presynaptic terminals (Sullivan, 2000; also present in small quantities in the Rutkowska and Jamontt, 2005; Tilley, several brain structures i.e.: hippocampus, 2011). , thalamus, and also into ventral Over the years, a number of tegmental area (Onaivi et al., population studies that focus on the CNR1 2006; Zhang et al., 2014). There is gene and polymorphisms selected because evidence that points to the role of CB2 of their possible impact on the receptor in addictive processes, for functionality of the CB1 receptor, example of (Navarrete et al., encoded by this gene (Albert, 2011). It is 2013). known that both the number encoded by Recently, there a growing number of the gene, CB1 receptors and their function new connections between the activity of can be changed in response to the altered the CB2 receptor and the occurrence of gene expression in various conditions or certain diseases. Furthermore, CB2 disease development, and in response to receptors are related with malignancies of contact with various substances, including the immune system and may serve as (Laprairie et al., 2012). potential targets for the induction of apoptosis. Also, because CB2 agonists Cannabinoid receptor type 2 – CB2 lack psychotropic effects, they may serve receptor as novel anticancer agents to selectively CB2 was first cloned from the human target and kill tumors of immune origin leukemia cell line HL-60 in 1993. The (Mc Kallip et al., 2002). Studies have receptor was identified among cDNAs shown, that the modulation of CB2 based on its similarity in amino-acid receptor signaling may represent a sequence to the CB1 receptor, discovered promising therapeutic target that can be in 1990. The discovery of CB2 helps to used to reduce neuronal degeneration in provide a molecular explanation for the neurodegenerative diseases, such as established effects of cannabinoids on the Parkinson's, Alzheimer's or Huntington's immune system. While the location of the disease (Cassano et al., 2017). CB2 CB1 receptor is mainly focused in the cannabinoid receptors expressed on , whereas CB2 malignancies of the immune system may receptor is positioned peripherally serve as potential targets for the induction (Befort, 2015). CB2 receptors are present of apoptosis (Herrera et al., 2006). primarily in the immune system: the Findings also indicate an increased risk of spleen, tonsils and in the cells of the schizophrenia for people with low CB2 immune system, particularly in B cells receptor function (Ishiquro et al., 2010). and NK cells (natural killers), as well as in The human CB2 receptor is composed T cells, monocytes, , mast of 360 amino acid residues and a and Hortegi cells (microglia). This molecular weight of about 40 kDa location of CB2 receptors indicates that (GeneCards). The CB2 receptor is a they are responsible for member of the G-protein-coupled immunomodulatory properties of receptor family. CB2 is also a single cannabinoids. There have also been polypeptide chain of seven hydrophobic reports about the presence of these transmembrane domains TM I to TM VII,

UNDERSTANDING CANNABINOID RECEPTORS: ACTION AND FUNCTION 5 FOLIA BIOLOGICA ET OECOLOGICA which have α-helis structure and pass have an extracellular, glycosylated N- through the cytoplasmic membrane. Its terminus and an intracellular C-terminus structure contains three extracellular and too (Figure 3.) (Konarska and Ellert, three intracellular loops. It was found to 2004).

Figure 3. Construction of cannabinoid receptor type 2 (CB2). The numbers at the beginning (1) and end (360) 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.

Most known cannabinoid compounds the molecular pathway by a signal from has a similar affinity for both receptor CB2 to MAPK may be also involved CB2 and CB1, despite differences in their p21/Ras, Raf-1 and MEK kinase amino acid structures. Compatibility (MAPKK), Anandamide is example for between the amino acid sequences of endogenously produced CB2 ligands these (CB1 and CB2) receptors in humans (Howlett and Mukhopadhyay, 2000; is 48%. It is worth noting that the coding Konarska and Ellert, 2004). sequences form CB2 are less conservative There is growing evidence that than the form CB1 (Konarska and Ellert, selective antagonists of the CB2 2004; Kazula, 2009). cannabinoid receptor inhibit or abolish The CB2 receptor is mainly associated most of the immunosuppressive effects of with the regulation of immune response cannabinoids. The cannabinoid ligands processes. Modification of the receptor may be potential therapeutic agent in activity is associated with impaired cell several pathophysiological situations, so proliferation and the generation of the the CB2 cannabinoid receptors have been defensive response modulators such widely studied in this direction. (Racz et cytokines. The CB2 receptor stimulation al., 2008). The researchers demonstrated, also results in the inhibition of adenylate that in contrast to the CB1 receptor, the cyclase (Konarska and Ellert, 2004). CB2 receptor activation does not affect Studies showed that in CHO (Chinese the ion channels (Pietrzak et al., 2011). hamster ovary) cells expressing CB2 The CB2 partly exerts its effects receptor, cannabinoids activate MAP through initiation of phospholipase C kinase. The CB2 receptor activation (PLC) and inositol 1, 4, 5-triphosphate passed through the MAPK is carried out (IP3) signaling pathways that lead to by G-protein subunits - γ and ß. One increased levels of intracellular calcium component of this pathway, in contrast to (Zoratti et al., 2003). the CB1 receptor is a C protein kinase. In

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Presumably novel cannabinoid glycosylation (Asn 604) (GeneBank; receptors GeneCards). TRPV1 usually occurs as a TRPV1 receptor homotetramer. Whereas it oligomerizes TRPV1 (transient receptor potential with other TRP receptors (e.g. TRPA1, cation channel subfamily V member 1) TRPV3) it functions as promiscuous belongs to the transient receptor potential channel (Staruschenko et al., 2010; Cui, (TRP) family, whose members act as ion 2016). TRPV1 in the solved state is channels. The TRP family is divided into composed of four symmetrical subunits, subfamilies: TRPC (canonical), TRPV and each of them consists of four (vanilloid), TRPM (melastatin), TRPP modules: in the transmembrane region – (polycystin), TRPML (mucolipin), TRPA the voltage sensor and pore domain and in (ankyrin) and TRPN (NOMPC-like). To the cytosol – N- and C-terminal modules date, more than 100 TRP-encoding genes (Fig. 4.) (Lee et al., 2015; Cui, 2016). The have been identified in animals (Clapham, central ion-conducting pore opens up, 2005; Nilius, 2011). when ligands are binding. In the N- TRPV1 is an integral membrane terminus occur six ankyrin (ANK) repeats protein, a non-selective cation channel (33 amino acids), which serve as binding that is gated by a broad array of noxious sites for inhibitors and allow interactions ligands (GeneBank; Cui, 2016). TRPV1 between proteins. There are also several affects on many functions including phosphorylation sites (Lishko et al., 2007; inflammation, painful stimuli sensation, Cui, 2016). The C-terminus contains a and mechanotransduction (Cui, 2016). TRP domain, which encompasses an α- The human TRPV1 gene is located on helix that runs parallel to the membrane. the short arm of chromosome 17 Moreover, there are a PIP2-binding site, (17p13.2). It consists of 19 exons, CaM-binding site, and several sites for includes 43 968 bases. The same protein phosphatases and kinases (Numazaki et is coding by four transcripts variant. The al., 2003; Garcia-Sanz et al., 2004; Cui, protein is composed of 839 amino acids 2016). In the structure of TRPV1 also and it can be subject to post-translational occur characteristic dual gates: G1 and modifications: phosphorylation by PKA G2, whose conformational changes lead (mainly Ser117), phoshphorylation by to entry into active state (Liao et al., 2013; CAMKII (regulate binding to ), Cui, 2016).

Figure 4. Construction of TRPV1 receptor. The numbers at the beginning (1) and end (839) of the chain indicate the direction of numbers of amino acids. Terminal residues, amino (N-) and carboxy (C-), transmembrane (TM I-VII) and others domains, intracellular (ic) and extracellular (ec) loops are also marked.

UNDERSTANDING CANNABINOID RECEPTORS: ACTION AND FUNCTION 7 FOLIA BIOLOGICA ET OECOLOGICA

Receptor activity is regulated in TRPV1 antagonists block the receptor response to the binding of specific ligands channels so they can be treated as an including CAPS, plant and toxins, promising therapeutic target. The first protons, heat. This is possible through the TRPV1 antagonist – , was gating mechanism, which involves created via modifying the chemical structural rearrangements within the backbone of natural agonist . channel. The result is a transition from the Antagonists are subdivided into two types: closed state (nonconducting) to open state competitive and noncompetitive. (conducting) (Hille, 1978; Cui, 2016). Competitive TRPV1 antagonists bind to the TRPV1 can be regulated in many ways active site and switch TRPV1 channel into via interactions with agonists or antagonists. closed state. Other competitive antagonists There are a lot of agonists that activate include cinnamide, quinazoline, TRVP1 channel. Anandamide was the first benzimidazole analogues. In turn, identified endogenous TRPV1 agonist antagonists like tetrabutylammonium and (Zygmunt et al., 1999). The group of thapsigargin, are classified as endogenous agonists includes also noncompetitive when they block pores in derived from the metabolism of arachidonic receptor by interacting with allosteric sites acid, N-arachidonoylethanolamine of the channel (Brito et al., 2014; Cui, 2016). (endocannabinoid), N- The functioning of the TRPV1 receptor arachidonoyldopamine (endocannabinoid), is involved into several physiological Noleoylethanolamine and N-acylsalsolinols functions, among others: thermo-sensation (Appendino, Minassi, Pagani, & Ech- (heat), autonomic thermoregulation, Chahad, 2008). Several endogenous , pain management, synaptic chemical substances also activate TRPV1: plasticity in the brain (long-term ammonia, adenosine, ATP, protons, ethanol, depression). TRPV1 is also involved in the and polyamines (Szallasi et al., 2007; Cui, endocannabinoid signaling in the brain 2016). TRPV1 is also induced by a plethora (Nilius, 2011). of nonselective stimuli, such as intracellular Furthermore, expression of the TRPV1 redox states, acidic pH (<5.3), heat (>43°C) gene is increased in many disorders. and electrostatic charge. CAPS (capsaicin, Researchers observed the altered expression the substance from hot chilli peppers) and of the TRPV1 in human preeclamptic RTX (the substance from corn) placenta (Martínez, 2016). TRPV1 is known belong to the natural TRPV1 agonists have to be expressed in peripheral sensory been studied clinically as potential neurons and at lower levels in the spinal treatments for inflammatory and cord, brain. Besides neurons, TRPV1 is also neuropathic pain. Furthermore, there are expressed a wide-range in non-neuronal several other naturally occurring agonists cells (e.g. keratinocytes, urothelium, T-cells, for TRPV1 channel including cannabinoids mast cells) (Martin, 2008). Therefore the (tetrahydrocannabinol (THC), cannabidiol role of TRPV1 in other pathological (CBD) and cannabinol (CBN) (Bisogno et diseases, for example respiratory- and al., 2001; Cui,2016). These findings suggest bladder-related diseases, , and that TRPV1 receptors might mediate some cancer (Cui, 2016). of the pharmacological effects of CBD and its analogues (Bisogno et al., 2001).

GPR55 (G protein-coupled receptor 55) It has been suggested that GPR55 is a GPCRs. This protein plays significant role novel cannabinoid receptor (Mackie and in signal transduction from the external Stella, 2006). It belongs to a G-protein- environment (GeneBank). coupled receptor superfamily, precisely to The human gene that encodes GPR55 the rhodopsin-like (ClassA) family of protein is located on the long arm of

8 ANDRZEJEWSKA A. ET AL. FOLIA BIOLOGICA ET OECOLOGICA chromosome 2 (2q37.1), encompasses receptor (GeneBank). The GPR55 is de- 53,910 bases and contains 4 exons. There orphanized as a cannabinoid receptor are 5 splice variants (GeneCards, (Shore and Reggio, 2015). GeneBank, Ensmbl). The GPR55 receptor The amino acid sequence is the most is consists of 319 amino acids and 7 similar to the GPR35 (27%), P2Y (29%), hydrophobic domains characteristic for GPR23 (30%), CXCR4 (26%) but also to GPRs. The molecular mass of the protein CB2 (14.4%) and CB1 (13.5%) receptors. is 36637 Da. (GeneCards, OMIM). It is an Amino acid structure of the human integral membrane protein and its GPR55 is shown on Figure 5. (Sawzdargo structure reminds structure of cannabinoid et al., 1999; Shore and Reggio, 2015).

Figure 5. Construction of GPR55 receptor. The numbers at the beginning (1) and end (319) 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.

Expression of GPR55 is very high in endocannabinoids as 2-AG, , large neurons. noladin ether, and Activation by defined cannabinoids in small increases amount of intracellular calcium concentrations and the atypical in these neurons. GPR55 activation also cannabinoids Cannabidiol and abnormal- inhibits potassium current through M-type cannabidol (synthetic regioisomer of potassium channels. It can suggests that cannabidiol). (Ryberg et al., 2007; Shore activation of GPR55 enhances neuronal and Reggio, 2015). excitability (Lauckner et al., 2008). Above findings establish GPR55 as an Expression of the GPR55 gene has been additional cannabinoid receptor that can observed also in the: central nervous activate signaling pathways distinct from system, adrenal glands, gastrointestinal CB1 or CB2, and that may increase tract, lung, liver, , bladder, kidney, neuronal excitability and can be involved and bone. The GPR55 receptor is also in nociception, particularly in neuropathic involved in regulation of energy intake or inflammatory pain states. (Ryberg et and expenditure. Therefore, this receptor al., 2007; Lauckner et al., 2008). plays a role in the maintenance of energy (Simcocks et al., 2014; Shore Summary and Reggio, 2015) In addition, Ryberg et The discovery of the cannabinoid al. analyzed GPR55 receptor ability to receptors in the 1990s led to the bind and to mediate GTPγS binding by characterisation of the endogenous cannabinoid ligands. This analysis cannabinoid system in the context of its showed that GPR55 is activated by composition and many fundamental

UNDERSTANDING CANNABINOID RECEPTORS: ACTION AND FUNCTION 9 FOLIA BIOLOGICA ET OECOLOGICA physiological functions. This day The use of cannabinoids is associated understanding of the cannabinoid with adverse side effects profile, their receptors and other receptors which binds action is non-specific, affects the entire cannabinoids ligands is still not yet fully central nervous system, causing dizziness, understood. The existence of additional drowsiness, difficulty in concentrating, cannabinoid receptors has long been sleep disturbances and thinking and vision suspected, due to the effects of some of disturbances. In addition, there are also the compounds causing cannabinoid-like hallucinations, psychosis, depression and effects on blood pressure and tachycardia. After prolonged use of these inflammation, but not activating CB1 and compounds there is a risk of developing a CB2 receptors. (Járai et al., 1999; tolerance to cannabinoids psychotropic McHugh et al., 2008) Reports suggest activity and any other side effects, which that, due to the fact of structural similarity causes significant reduction of the of GPR55 to CB1 and CB2 and sequence therapeutic indications (Karjnik and homology should be characterized as a Żylicz, 2008) Therefore, more hope for third cannabinoid receptor (Ryberg et al. the use of cannabinoids compounds 2007; Johns et al., 2007) involves the treatment of Cannabinoids have a wide spectrum of pathophysiological mechanisms which activity, it exhibits the properties for closely correlate with the antiinflammatory, neuroprotective, endocannabinoid system. There are also antiemetic and effects (McHugh suspicions that a deeper understanding of et al., 2008). Studies suggested that they receptors interacting with cannabinoids can also relieve intraocular pressure and its interconnections with the (benefit for glaucoma patients) and have cardiovascular system may be important an anti-proliferative effect on cancer cells. in the prevention and treatment of According to the National Institute of diseases of this system (Kazula2009). One Health cannabinoids-based medications way of overcoming the problems studies are concentrated on multiple associated with the side effect of sclerosis research, chronic obstructive cannabinoids may be compounds which pulmonary disease, sickle cell disease, potentiate the action of endogenous spinal cord injury pain, inflammatory cannabinoids or influence the cannabinoid bowel disease (Crohn’s disease), cancer- system indirectly. In this context, gain related pain and brain tumors (U.S. greater knowledge of receptors interacting National Institutes of Health, 2013. with cannabinoids seems to be extremely https://clinicaltrials.gov). valuable.

Funding This work was supported financially by The National Centre for Research and Development (Grant Number INNOMED/I/ 11/NCBR/2014) from the Innovative Economy Operational Programme founds, in the framework of the European Regional Development Fund.

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Streszczenie Układ endokannabinoidowy (ang. endocannabinoid stystem-ECS) składa się z receptorów kannabinoidowych CB1 i CB2, agonistów egzogennych i endogennych: kannabinoidów i endokannabinoidów oraz enzymów regulujące syntezę i degradację endogennych ligandów tego układu. Jest systemem biorącym udział w wielu procesach fizjologicznych organizmu. Odgrywa on istotną rolę w prawidłowym funkcjonowaniu centralnego i autonomicznego układu nerwowego. Układ endokannabinoidowy reguluje również m.in. gospodarkę energetyczną, aktywność motoryczną, układ endokrynny oraz układ hormonalny poprzez regulacje powiązań neurohormonalnych i neuroimmunologicznych. Wiele jego wspomnianych funkcji związanych jest z receptorami sprzężonymi z białkami G, takimi jak receptory CB1, CB2 czy GPR55. Co raz więcej mówi się również o znaczącej roli receptorów przejściowego potencjału TRPs (ang. transient receptor potential), które nie tylko pośredniczą w odczuwaniu bólu, ale także są odpowiedzialne za wspomaganie stanu zapalnego poprzez wydzielanie pro- zapalnych neuropeptydów. W niniejszej pracy przeglądowej postanowiliśmy krótko scharakteryzować oraz opisać rolę i działanie receptorów kannabinoidowych CB1 i CB2, receptora sprzężonego z białkiem G (GPR55) i receptora przejściowego potencjału waniloidowego (TRPV1).

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