Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Type-1 Cannabinoid Receptor

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101565


Historical Background

The use of cannabis (Cannabis sativa) has been known for centuries, but it was necessary to wait until the late 1980s to understand the molecular basis responsible for its medical and recreational properties. Unlike cocaine and morphine, isolated as crystalline salts from coca leaves and opium respectively, the active constituent of cannabis appeared as an oily extract, difficult to isolate in pure form. Only in the 1960s isolation, characterization, and chemical synthesis of the active cannabis constituent, Δ9-tetrahydrocannabinol (THC), was possible. The identification of THC allowed a reevaluation of cannabis pharmacology and gradually boosted research towards the understanding of the molecular and cellular mechanisms underlying its therapeutic efficacy.

Although the existence of THC-binding cannabinoid receptors, and of an even more surprising ensamble of metabolic enzymes and transporters that form the “endocannabinoid system” (eCS) is now widely accepted, at least two main assumptions hampered research in this arena. Firstly, identification of type-1 cannabinoid receptor (CB1) was slowed down by the presumed lack of stereoselectivity of THC. Indeed, it is generally expected that an enzyme or a receptor recognizes and binds to its substrate or ligand with a very high degree of stereoselectivity. Apparently, THC lacked this peculiar feature, as synthetic (+)-THC showed the same cannabimimetic activities of the natural (−)-THC. Only later on the improvement of the analytical methods necessary for the separation of enantiomers was able to demonstrate the intrinsic stereoselectivity of THC. Furthermore, being lipophilic THC was thought to act directly via biological membrane perturbation (Mechoulam et al. 1998). Yet, structure–activity relationship studies indicated that small modifications in the chemical structure of THC led to new derivatives endowed with significantly different activity, a finding that is incompatible with a membrane perturbing effect only. Moreover, the discovery that THC inhibited adenylyl cyclase (AC) in a way independent of muscarinic, α2-adrenergic, and opiate receptors provided strong evidence for a specific receptor mediating THC actions. Stereospecificity of cannabinoids like THC to inhibit AC was further confirmed by using synthetic HU-210 and HU-211 enantiomers.

These pioneeristic research efforts culminated in the discovery of SKR6, an orphan G protein-coupled receptor (GPCR) derived from a rat cerebral cortex cDNA library, identified as the first type of cannabinoid receptor, now termed CB1 (Matsuda et al. 1990). Subsequently, CB1 was cloned from human and mouse samples, and the deorphanization of CX5, another GPCR expressed in the human leukemic cell line HL60, led to the identification of a type-2 cannabinoid receptor, named CB2. Nomenclature to denote these two cannabinoid receptors will be adopted throughout this review as recommended by The Committee on Receptor Nomenclature and Drug Classification of the International Union of Basic and Clinical Pharmacology, IUPHAR (Pertwee et al. 2010).

CB1 Structure and Signaling

The human gene encoding for CB1 (CNR1) has been localized in chromosome 6 to position 6q14–q15. The genes encoding for mouse and rat CB1 were found on chromosomes 4 and 5, respectively. CNR1 contains four exons (Fig. 1), and the protein-coding region sits entirely in exon 4 with variations in the length of the 5′ untranslated region (UTR).
Type-1 Cannabinoid Receptor, Fig. 1

Schematic representation of CNR1 position on human chromosome 6 and of its different exons

This 5′UTR can be alternatively spliced or transcribed at different sites to yield different transcripts with region-specific expression in the brain. Two splice variants of human CNR1, that encode for CB1 isoforms CB1a and CB1b, have been described but their localization, distribution, and ligand affinity remain as yet to be clarified (Laprairie et al. 2012). CNR1 genes encode for proteins of 472 (human) or 473 (rat, mouse) amino acids, including a rather long and well-conserved amino terminal extracellular domain. Overall, these three receptors have 97–99% amino acid sequence identity. CB1 belongs to the subgroup A13 of Class A (rhodopsin (Rho) family) of GPCRs. The general topology of a Class A GPCR includes: (i) an extracellular N-terminus (generally glycosylated); (ii) seven transmembrane (TM) α helices (Hs), interconnected by three intracellular loops (I1-I3) and three extracellular loops (E1-E3); and (iii) an intracellular C-terminus that begins with a short helical segment (Helix 8) oriented in parallel to the membrane surface (Laprairie et al. 2012). These features are schematically shown in Fig. 2.
Type-1 Cannabinoid Receptor, Fig. 2

CB1 structure. (a) Amino acid sequence of human CB1. Colors highlight amino acids present in extracellular (red), transmembrane (light blue), and cytoplasmic (green) regions, respectively. (b) Graphical representation of CB1 structure

Several agonists functionally activate CB1, and according to their chemical structures they fall essentially in four classes (Fig. 3). Classical cannabinoids consist of ABC-tricyclic dibenzopyran derivatives and are either plant-derived cannabinoids (phytocannabinoids) or their synthetic analogues (synthocannabinoids). The best studied compounds of these two classes are THC itself, Δ8-THC, and the synthetic cannabinoid (6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a–tetrahydro-1-hydroxy-6,6-dimethyl-6Hdibenzo[b,d]pyran-9-methanol (HU-210). Nonclassical cannabinoids have quite similar chemical structure to classical cannabinoids. They consist of AC-bicyclic and ACD-tricyclic analogues of THC that lack a pyran ring, and (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP 55940), considered as the prototypic member of this group, is known to bind to both CB1 and CB2 with similar affinity. The aminoalkylindole group, typified by R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212–2), contains compounds that are structurally different from classical or nonclassical cannabinoids. The fourth group includes endogenous cannabinoids (endocannabinoids, eCBs), of which N-acylethanolamines (NAEs) and acylesters are the best-studied members. In particular, N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) are the two most prominent representatives of NAEs and acylesters, respectively, and show a rather low binding activity towards CB2 compared to CB1 (Pertwee et al. 2010).
Type-1 Cannabinoid Receptor, Fig. 3

Chemical structures of different prototypes of the four classes of CB1 agonists

Mutagenesis analysis and computational modeling studies for CB1 have been performed in quite some detail, and residues responsible for ligand binding as well as for receptor stabilization and activation have been identified (Shim 2010). Of note, tyrosine Y275 and phenylalanine F189 residues are important for AEA binding to CB1, and docking models suggested that F189 indeed interacts directly with the C5-C6 double bond of AEA via aromatic/π interaction (Shim 2010). Moreover, lysine K192 was highlighted as one of the key residues for AEA, CP55940, and SR141716A (but not WIN55212–2) binding, via a mechanism of action that involves an indirect modification of the geometry of the ligand-binding pocket rather that a direct interaction with different residues. In addition, CB1 lacks the conserved disulfide bond between cysteine residues (C110 and C187) from H3 and E2, important for maintaining receptor structure and function. Only other two cysteine residues (C257 and C264), present on the second extracellular loop (E2) that connects H4 and H5, are required for high-level expression and receptor activity, by forming an intra-loop disulfide bond. Several domains important for regulation of CB1 signaling have been identified. Two serines (S426 and S430) are required for rapid desensitization of CB1-activated extracellular signal-regulated kinase (ERK) 1/2 signaling, and S317 is the site of protein kinase C phosphorylation (Shim 2010).

Activation of CB1 by its ligands triggers multiple signal transduction pathways that depend on the coupled G protein subclass (Turu and Hunyady 2010; Pertwee et al. 2010), as schematically represented in Fig. 4.
Type-1 Cannabinoid Receptor, Fig. 4

Main signal transduction pathways triggered by CB1 activation

Inhibition of AC activity was the first agonist-stimulated, Gi/o-dependent CB1 signal transduction pathway to be characterized, leading to protein kinase A (PKA) inhibition. In addition, stimulation of CB1 activates, again through Gi/o proteins, different members of the mitogen-activated protein kinase (MAPK) family, such as ERK1/2, c-Jun N-terminal kinase (JNK), and p38 MAPK. Also, phosphatidylinosityl-3-kinase (PI3K) and focal adhesion kinase (FAK) signaling is triggered by CB1, yet via unidentified G proteins. Moreover, CB1 inhibits voltage-gated Ca2+ channels (L, N, and P/Q type) and activates the inward rectifying K+ channels, likely via Go proteins. It has been also reported that under certain circumstances CB1 can be couple to Gs proteins and stimulate cAMP formation (Turu and Hunyady 2010; Pertwee et al. 2010).

CB1 Homomers and Heteromers

Only little evidence supports the existence of CB1 homomers, but no information at all is available on their potential effects on signal transduction or trafficking patterns. However, association between CB1 and several other GPCRs to form heteromeric complexes (CB1-X), where the functional interactions influence ligand selectivity or relative intrinsic activity, have described (Pertwee et al. 2010)

Direct evidence for the heteromeric complexes of CB1 associated with either δ or μ opioid receptors (DOR and MOR, respectively) derived from protein interaction assays performed in live cells, such as fluorescence and bioluminescence resonance energy transfer (FRET and BRET). Coexpression of MOR with CB1 in HEK-293 cells significantly increased BRET signal, and activation of CB1 by selective agonists reduced morphine-mediated [35S]-GTPγS binding. In Neuro-2A cells, coactivation of MOR and CB1 attenuated neurite outgrowth, as well as the levels of phosphorylated Src and of signal transducers and activators of transcription (STAT)-3. Moreover, coimmunoprecipitation and Western blotting analyses confirmed the heterodimers of MOR and CB1, and immunofluorescence studies demonstrated colocalization of DOR with CB1 in cortical neurons (Pertwee et al. 2010; Rozenfeld et al. 2012). Heteromerization affects receptor signaling, since the potency of CB1 ligands to stimulate G-protein activity increases or decreases in the absence or presence of DOR, respectively (Rozenfeld et al. 2012). DOR and CB1 expression increased in the cortex of a rodent model of neuropathic pain, and activation of G-protein-mediated signaling via CB1 increased while that of a DOR-selective agonist decreased, overall suggesting that CB1 activation may suppress DOR activity (Bushlin et al. 2012). In addition, CB1 can allosterically modulate DOR ligand binding and activity, as treatment with CB1 antagonist PF-514273, or with a low dose of CB1 agonist HU210, restored cortical DOR activity (Bushlin et al. 2012).

The first evidence for a cross-talk between CB1 and orexin type-1 receptor (OX1R), a protein implicated in the regulation of the feeding behavior, was reported in CHO cells. Overexpression of both receptors enhanced OX1-mediated activation of the MAPK pathway, an effect that was reverted by SR141716 and was observed only in presence of CB1 (Pertwee et al. 2010). Such an intersection was further demonstrated in HEK293 cells, where CB1-OX1R heteromerization influences translocation of both receptors to the cell surface. More recently, the formation of CB1-OX1R heteromers has been reported also in embryonic mouse hypothalamic NPY/AgRP mHypoE-N41 neurons, which express constitutively both CB1 and OX1R, upon incubation with neuropeptide orexin A alone or in combination with CB1 agonist ACEA (Imperatore et al. 2016). CB1-OX1R formation was reverted by an OX1R or CB1 antagonist, SB-334867 or AM251, respectively, and did not revert after ACEA incubation. Moreover, formation of heteromeric complexes modulates intracellular calcium concentration, ERK phosphorylation, and synthesis of 2-AG (Imperatore et al. 2016).

CB1 and dopamine receptor 2 (D2) complexes were also reported. CB1-D2 formation can be promoted by agonists of each receptor, and modulates CB1 signaling from a pertussis toxin-sensitive inhibition to a partly pertussis toxin-insensitive stimulation of AC and ERK1/2 phosphorylation. In rat striatal membrane preparations, CB1 agonist CP 55,940 reduced the affinity of D2 agonist binding sites, and antagonistic CB1/D2 interactions drive behavior, because CP 55,940 blocks the quinpirole-induced increase in locomotor activity (Pertwee et al. 2010). BRET analysis highlighted that CB1 and D2 heteromerize when expressed in striatal embryonic progenitor cells, STHdhQ7/Q7. Moreover, D2 antagonism can allosterically inhibit the association of CB1 and Gαi protein, because haloperidol reduces ACEA-mediated Gαi-dependent ERK phosphorylation. Finally, D2 antagonism was reported to inhibit CB1 agonist-induced recruitment of β-arrestin1 to CB1, as well as internalization of CB1 itself (Bagher et al. 2016).

Physical interactions have been documented also between adenosine A2A receptor (A2AR) and CB1, to form heteromeric complexes in cotransfected HEK293 cells and in rat striatum, where a low dose of the A2A antagonist MSX-3, devoid of any motor effect by itself, counteracts the motor depressant effects produced by CB1 activation. Positive or negative interaction for A2AR and CB1 have been reported (Pertwee et al. 2010; Ferreira et al. 2015), and the physiological relevance of pre- or postsynaptic CB1 localization to cross talk with A2AR has been reviewed (Ferré et al. 2014). More recently, a transgenic rat strain, NSEA2A rats, overexpressing A2AR under the control of the neural-specific enolase promoter, and forming CB1-A2AR heteromers in striatal glutamatergic terminals (Ferreira et al. 2015), has been used to study the role of A2AR heteromers in striatal functions (Chiodi et al. 2016). It was reported that the effects mediated by CB1 activation on synaptic transmission and motor activity were significantly reduced in the striatum of NSEA2A compared to wild-type rats. Consistently, A2AR antagonists failed to revert the CB1 agonist-mediated effects in NSEA2A but not in wild-type animals. In the same model, the overexpression of A2AR does not modify striatal CB1 levels but might unbalance the stoichiometry of A2AR and CB1, thus reducing the formation of CB1-A2AR heteromers (Chiodi et al. 2016).

Finally, formation of heteromers between CB1 and angiotensin II type 1 receptor, as well as between CB1 and CB2, has been also documented and awaits for further clarification.

CB1 Polymorphisms

Since its identification, CB1 has been widely investigated as potential target to develop new therapeutic strategies. Thus, alterations of CB1 expression, binding and/or signal transduction in relation to both central and peripheral human diseases have been the subject of intense research efforts. Moreover, many studies revealed that single nucleotide polymorphisms (SNPs) of the CB1-encoding gene CNR1 correlate with a number of human behaviors and/or disease conditions (Table 1) (Pertwee et al. 2010; Vasileiou et al. 2013).
Type-1 Cannabinoid Receptor, Table 1

Main CB1 polymorphisms and association with human disorders




Disease association




Anorexia nervosa

Bulimia nervosa

Metabolic syndrome

Ulcerative colitis

Crohn’s disease

Hebephrenic schizophrenia


Posttraumatic stress disorders

NAFLD in women with polycystic ovary syndrome




Triglyceride and cholesterol levels

Metabolic syndrome




NAFLD in women with polycystic ovary syndrome

Triglyceride and cholesterol levels

Cocaine dependence and cocaine induced paranoia

Cannabis dependence

Alcohol dependence




Cocaine dependence and cocaine induced paranoia

Alcohol dependence

NAFLD in women with polycystic ovary syndrome




Smoking initiation and nicotine dependence

A family-based study suggests that anorexia nervosa (AN) may be associated with the number of ATT repeats of CNR1 promoter, and the A allele of intragenic SNP of CNR1, rs1049353, was associated with a moderate risk to develop AN and bulimia nervosa in Caucasian patients. Interestingly, rs1049353 was also associated with metabolic syndrome and with specific macronutrient intake and low cholesterol levels in obese females, as well as with diabetic nephropathy and retinopathy in patients affected by type 2 diabetes (Pertwee et al. 2010; Vasileiou et al. 2013; Buraczynska et al. 2014). Genotypization of six SNPs of CNR1 in 1560 Caucasian individuals highlighted that SNP rs806366, located in the 3-untranslated region, and SNP rs806368 in the coding exon 4 were associated with altered triglyceride levels. Moreover, subjects A/A homozygous for the CNR1 rs1049353 showed a reduced risk to develop ulcerative colitis, while G/G homozygous were more likely to develop Crohn’s disease before 40 years of age. Variation in (AAT)n repeat of the CNR1 promoter conferred an increased risk for developing irritable bowel syndrome (Pertwee et al. 2010; Vasileiou et al. 2013; Jiang et al. 2014), as well as aggravated symptoms in multiple sclerosis patients (Rossi et al. 2013). Additionally, rs1049353 impacts on insulin resistance and adipokine profile in patients with nonalcoholic fatty liver disease (NAFLD), while rs806368, rs12720071, rs1049353, rs806381, rs10485170, and rs6454674 were associated with NAFLD frequency in women with polycystic ovary syndrome (Kuliczkowska Plaksej et al. 2014).

Two SNPs in CNR1, namely rs6454674 and rs806368, were found to be associated with cocaine dependence and cocaine-induced paranoia across independent populations of European and African Americans, as well as in African descents. The same SNPs were associated with alcohol and illicit drug dependence in European Americans, and rs806368 demonstrated an association with cannabis dependence (Pertwee et al. 2010; Vasileiou et al. 2013). Meta-analysis of 13 studies on rs1049353, rs806379 and the (AAT)n repeat association with illicit substance dependence showed that only the (AAT)n polymorphism in the Caucasian population showed a significant association with dependence, when using a risk allele definition ≥ 16 repeats. More recently, a negative association of rs1049353 and susceptibility to cannabis addiction in a Turkish population has been also reported (Isir et al. 2016), and the role of a familial risk of cannabis use and dependence has been investigated (Hill et al. 2016). In particular, a prospective longitudinal study spanning from childhood to young adulthood investigated cannabis use behaviors of 338 young adults, and correlate genetic variation in CNR1 and D2 as potential predictors of cannabis use or abuse/dependence. This study highlighted that CNR1 variations were not associated with the frequency of use (Hill et al. 2016). It should be recalled that some studies failed to reveal associations between schizophrenia and rs1049353, rs77660229, rs86366, and rs6454674, whereas the (AAT)n CNR1 microsatellite are related to schizophrenia vulnerability, independent of substance abuse, in a Spanish population (Pertwee et al. 2010; Vasileiou et al. 2013). Moreover, rs1049353 has been associated with predisposition to the hebephrenic schizophrenia subtype, and rs2501431 and rs1049353 SNPs have been linked to depression. Finally, rs6928499, rs1535255, and rs2023239 were nominally associated with a lower risk to develop metabolic syndrome in schizophrenic patients, and studies of cannabis use in the same type of patients identified specific variants of CNR1 (rs12199654 and rs2023239), that are related to reductions in brain white matter volume (Pertwee et al. 2010; Vasileiou et al. 2013).


The discovery of THC more than 50 years ago and the identification of its target receptor CB1 in 1990 can be considered as two milestones that boosted joint efforts of scientists with different expertise to clarify the role of CB1 in human pathophysiology. CB1 is an integral and key component of the very complex “endocannabinoid system” that modulates several functions in the central nervous system, as well as at the periphery. This review has summarized current understanding of the structural and molecular mechanisms underlying CB1 function, with a focus on CB1 dimerization and genetic polymorphisms that are correlated with human disease conditions.


  1. Bagher AM, Laprairie RB, Kelly ME, Denovan-Wright EM. Antagonism of dopamine receptor 2 long affects cannabinoid receptor 1 signaling in a cell culture model of striatal medium spiny projection neurons. Mol Pharmacol. 2016;89:652–66.PubMedCrossRefGoogle Scholar
  2. Buraczynska M, Wacinski P, Zukowski P, Dragan M, Ksiazek A. Common polymorphism in the cannabinoid type 1 receptor gene (CNR1) is associated with microvascular complications in type 2 diabetes. J Diabetes Complications. 2014;28:35–9.PubMedCrossRefGoogle Scholar
  3. Bushlin I, Gupta A, Stockton Jr SD, Miller LK, Devi LA. Dimerization with cannabinoid receptors allosterically modulates delta opioid receptor activity during neuropathic pain. PLoS One. 2012;7:e49789.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Chiodi V, Ferrante A, Ferraro L, Potenza RL, Armida M, Beggiato S, Pèzzola A, Bader M, Fuxe K, Popoli P, Domenici MR. Striatal adenosine-cannabinoid receptor interactions in rats over-expressing adenosine A2A receptors. J Neurochem. 2016;136:907–17.PubMedCrossRefGoogle Scholar
  5. Ferré S, Casadó V, Devi LA, Filizola M, Jockers R, Lohse MJ, Milligan G, Pin JP, Guitart X. G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol Rev. 2014;66:413–34.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Ferreira SG, Gonçalves FQ, Marques JM, Tomé ÂR, Rodrigues RJ, Nunes-Correia I, Ledent C, Harkany T, Venance L, Cunha RA, Köfalvi A. Presynaptic adenosine A2A receptors dampen cannabinoid CB1 receptor-mediated inhibition of corticostriatal glutamatergic transmission. Br J Pharmacol. 2015;172:1074–86.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Imperatore R, Palomba L, Morello G, Spiezio AD, Piscitelli F, Marzo VD, Cristino L. Formation of OX-1R/CB1R heteromeric complexes in embryonic mouse hypothalamic cells: Effect on intracellular calcium, 2-arachidonoyl-glycerol biosynthesis and ERK phosphorylation. Pharmacol Res. 2016;111:600–9.PubMedCrossRefGoogle Scholar
  8. Hill SY, Jones BL, Steinhauer SR, Zezza N, Stiffler S. Longitudinal predictors of cannabis use and dependence in offspring from families at ultra high risk for alcohol dependence and in control families. Am J Med Genet B Neuropsychiatr Genet. 2016;171B:383–95.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Isir AB, Baransel C, Nacak M. An information theoretical study of the epistasis between the CNR1 1359 G/A polymorphism and the Taq1A and Taq1B DRD2 polymorphisms: assessing the susceptibility to cannabis addiction in a Turkish population. J Mol Neurosci. 2016;58:456–60.PubMedCrossRefGoogle Scholar
  10. Jiang Y, Nie Y, Li Y, Zhang L. Association of cannabinoid type 1 receptor and fatty acid amide hydrolase genetic polymorphisms in Chinese patients with irritable bowel syndrome. J Gastroenterol Hepatol. 2014;29:1186–91.PubMedCrossRefGoogle Scholar
  11. Kuliczkowska Plaksej J, Laczmanski L, Milewicz A, Lenarcik-Kabza A, Trzmiel-Bira A, Zaleska-Dorobisz U, Lwow F, Hirnle L. Cannabinoid receptor 1 gene polymorphisms and nonalcoholic fatty liver disease in women with polycystic ovary syndrome and in healthy controls. Int J Endocrinol. 2014;2014:232975.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Laprairie RB, Kelly ME, Denovan-Wright EM. The dynamic nature of type 1 cannabinoid receptor (CB(1)) gene transcription. Br J Pharmacol. 2012;167:1583–95.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346:561–4.PubMedCrossRefGoogle Scholar
  14. Mechoulam R, Fride E, Di Marzo V. Endocannabinoids. Eur J Pharmacol. 1998;359:1–8.PubMedCrossRefGoogle Scholar
  15. Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev. 2010;62:588–631.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Rossi S, Bozzali M, Bari M, Mori F, Studer V, Motta C, Buttari F, Cercignani M, Gravina P, Mastrangelo N, Castelli M, Mancino R, Nucci C, Sottile F, Bernardini S, Maccarrone M, Centonze D. Association between a genetic variant of type-1 cannabinoid receptor and inflammatory neurodegeneration in multiple sclerosis. PLoS One. 2013;8:e82848.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Rozenfeld R, Bushlin I, Gomes I, Tzavaras N, Gupta A, Neves S, Battini L, Gusella GL, Lachmann A, Ma'ayan A, Blitzer RD, Devi LA. Receptor heteromerization expands the repertoire of cannabinoid signaling in rodent neurons. PLoS One. 2012;7:e29239.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Shim JY. Understanding functional residues of the cannabinoid CB1. Curr Top Med Chem. 2010;10:779–98.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Turu G, Hunyady L. Signal transduction of the CB1 cannabinoid receptor. J Mol Endocrinol. 2010;44:75–85.PubMedCrossRefGoogle Scholar
  20. Vasileiou I, Fotopoulou G, Matzourani M, Patsouris E, Theocharis S. Evidence for the involvement of cannabinoid receptors’ polymorphisms in the pathophysiology of human diseases. Expert Opin Ther Targets. 2013;17:363–77.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Endocannabinoid Research GroupInstitute of Biomolecular Chemistry, National Research CouncilPozzuoliItaly
  2. 2.Department of MedicineCampus Bio-Medico University of RomeRomeItaly
  3. 3.European Center for Brain Research/IRCCS Santa Lucia FoundationRomeItaly