chapter 58 - cannabinoids and the cannabinoid receptors ......way how the precursors are chemically...

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Handbook of Cannabis and Related Pathologies. http://dx.doi.org/10.1016/B978-0-12-800756-3.00068-5Copyright © 2017 Elsevier Inc. All rights reserved.

58Cannabinoids and the Cannabinoid

Receptors: An OverviewD. Lu, D.E. Potter

Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX, United States

SUMMARY POINTS

• Cannabinoidsareagroupofbiologicallyactiveingredientsisolatedfromcannabis.Therepresentativememberofcannabinoidsis(−)-∆9-tetrahydrocannabinol(∆9-THC),whichbindstocannabinoidreceptorstoexertitsbiologicaleffects,includingpsychoactiveeffects.

• Sofar,atleasttwotypesofcannabinoidreceptorshavebeenidentifiedanddefinedrespectivelyascannabinoidreceptor1(CB1)andcannabinoidreceptor2(CB2),whichareG-proteincoupledreceptorsspecificallyrespondingtophytocannabinoids,endocannabinoidsandsyntheticcannabimimeticcompounds.

• Thecannabinoidreceptorsarewidelydistributed.TheCB1receptorsareprimarilyfoundinthecentralnervoussystem,whereastheCB2receptorsaremainlyfoundinthecellsofimmuneandhematopoieticsystems.

• ActivationsofthecannabinoidCB1andCB2receptorsgenerallyleadtotheinhibitionofadenylylcyclase,andtheactivationofmitogen-activatedproteinkinases(MAPKs).

• Thecannabinoidreceptorsareinvolvedinalargenumberofphysiologicalprocesses,suchasneuronaldevelopment,foodintakeandenergybalance,perceptionprocess,andimmunemodulation.

KEY FACTS• Accordingtoworldhealthorganization,about

147millionpeopleworldwide(2.5%oftheworldpopulation)consumecannabismainlyforrecreationalpurposes.

• Bothshort-termandlong-termusesofcannabishavebeenlinkedtocertainhealthhazardssuchasalteredsenses,impairedbodymovement,memory,andlearningfunctions.

• Somesyntheticcannabis-mimeticsaremorepotentthannaturalcannabisingredients.Theymayaffectthebodyfunctionsmuchmorepowerfullythancannabis.Theiractualeffectsareunpredictable.Insomecases,theycanbeevenlife-threatening.

• Whilecannabisisanillicitdrug,ithasbeendemonstratedwithanumberofpotentialmedicalusefulnessincludingtreatmentofasthmaandglaucoma,asanantidepressant,appetitestimulant,anticonvulsant,antispasmodic,antiemetic,andanalgesic.

• Byfar,threecannabis-basedmedicationshavebeendeveloped,whichincludeDronabinol®,Cesamet®,andSativex®.ThefirsttwowereprovedbyFDAforthetreatmentofnauseaandvomitingintheadvancedstagesofcancerandAIDS,whilstSativex®wasapprovedinsomeEuropeancountriesforthetreatmentofspasticityfrommultiplesclerosis.

• ByfarintheUnitedSates,25statesandWashingtonD.C.havelegalizedcannabisformedicaluses.

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LIST OF ABBREVIATIONS

∆9-THC (−)-∆9-TetrahydrocannabinolAP-3 Adaptorproteincomplex-3BC BeforeChristcAMP CyclicadenosinemonophosphateCB1 Cannabinoidreceptortype1CB2 Cannabinoidreceptortype2cDNA ComplementaryDnACHO ChinesehamsterovaryCNS CentralnervoussystemDNA DeoxyribonucleicacidFAAH FattyacidamidehydrolaseFAN Factorassociatedwithneutral

sphingomyelinaseactivationG-protein Guaninenucleotide-bindingproteinGABA γ-AminobutyricacidGASP1 GPCr-associatedsortingprotein1GPCR G-protein-coupledreceptorJNK C-Junn-terminalkinaseMAGL MonoacylglycerollipasePI3K Phosphatidylinositide3-kinaseTM Transmembrane

INTRODUCTION

Cannabis has a long history for medical applica-tion, and is a psychoactive substance for recreationaluse. Isolation of its major active components (canna-binoids) and the synthesis of potent cannabimimeticsledtothediscoveriesoftwoG-proteincoupledrecep-torsthatspecificallyrespondtocannabinoids,andaredesignated as cannabinoid receptor 1 (CB1) and can-nabinoid receptor 2 (CB2). Subsequently, endogenousligands for the cannabinoid receptors (endocannabi-noids)wereidentified.Thecannabinoidreceptorsandthe endocannabinoids are involved in modulation ofmany physiological functions, not only in the centralandperipheralnervoussystems,butalsoinanumberofperipheral siteswithin thehumanbody:endocrinesystem,immunesystem,thegastrointestinaltract,car-diovascularsystem,andthereproductivesystem.Thetwo described cannabinoid receptors are encoded bydifferent genes, and exhibit a 44% homology in theirprimarystructures.Functionally,theybelongtothesu-per family of G-protein coupled receptors, and trans-ducesignalsof ligandbinding intovariousbiologicalresponses, through both G-protein-mediated andG-protein-independentpathways.

Generally, the major role of the CB1 receptor is tomodulatethereleaseofneurotransmitters,whereasthemajor function of the CB2 receptor is to mediate theimmune modulatory effects of cannabinoids, amongothers.The functionsof cannabinoidreceptorscanbe

modulated by: (1) a variety of ligands (agonists, par-tialagonists,neutralantagonists,andinverseagonists)that target the orthosteric binding sites on the recep-tors,or(2)allostericmodulatorsthatbindtothealloste-ricbindingsitesofthereceptors.Withthedevelopmentof a variety of new ligands of cannabinoid receptors,intensiveresearchhasbeencarriedoutinthelasttwodecadestoclarifytherolesofcannabinoidreceptorsinphysiological and pathological conditions, as well astodeterminehowthediseasestatesinvolvingthecan-nabinoidreceptorscanbetreatedmoreeffectivelyandsafely.Inthischapter,somehistoricalandfundamentalaspectsaboutcannabinoidsandcannabinoidreceptorsarereviewed.

CANNABIS AND CANNABINOIDS

The plant Cannabis sativa linne is one of the oldestplantsusedbyhumansasfolkloremedicine.Theearli-estrecordofmedicaluseofcannabisappearedaround2737 BC in a Chinese pharmaceutical compendium,Shennong Bencao Jing (The Divine Farmer’s MateriaMedica),inwhichCannabiswasdocumentedasamagicmood-andmemory-booster,anantiinflammatoryherb,andasatherapeuticformanyotherconditions,includ-ingdisordersofthefemalereproductivetract,constipa-tion,gout,rheumatism,stroke,andabsent-mindedness(yang,1998).Duringthelonghistoryofagriculturalmi-grationofcannabisfromChinaandIndiatotheMiddleEastandEurope,variousmedicalusefulnessofcanna-bis have been noted (Mack & Joy, 2000). In 1850, can-nabiswas included in theUSpharmacopeia formanyailments, including neuralgia, tetanus, typhus, chol-era, rabies, dysentery, alcoholism, opiate addiction,anthrax, leprosy, incontinence, gout, convulsive dis-orders, tonsillitis, insanity, excessive menstrual bleed-ing, and uterine bleeding (Boire & Feeney, 2006). Thebroad pharmacological effects of cannabis stimulatedthe search for its bioactive ingredients, and led to theisolationandstructuralcharacterizationof(−)-∆9-trans-(6aR,10aR)-tetrahydrocannabinol (∆9-THC) in 1964(Gaoni & Mechoulam, 1964). ∆9-THC is the most psy-choactive substance present in cannabis. To date, 489constituentshavebeenisolatedfromcannabis(Elsohly& Slade, 2005). These natural compounds can be clas-sified into 18 distinct chemical groups such as canna-binoids (∼70), terpenoids (∼103),hydrocarbons (∼50),amino acids (∼18), steroids (∼11), and flavaniidglyco-sides(∼19),amongothers(Elsohly&Slade,2005;Turner,Elsohly,&Boeren,1980).Cannabinoidsisagroupof70terpenophenolic compounds that generally contain amonoterpenemoiety connected toaphenol ring,hav-inga3-to5-carbonalkylchainlocatedinthepositionmetatothephenolichydroxylgroup.Thereare12major

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types of cannabinoids, all of which are derived fromcannabigerol typeprecursors,anddiffermainly in thewayhowtheprecursorsarechemicallycyclizedwithinthe structure.The representativemembersof cannabi-noidsareillustratedinFig.58.1.

The discoveries of endogenous cannabinoids (endo-cannabinoids) and the development of synthetic can-nabimimetic compounds have prompted the use of“phytocannabinoids” to describe plant-derived cannabi-noids.Amongthesephytocannabinoids,(−)-∆9-THC(1)and

(−)-∆8-THC(2)aretwopsychologicallyactiveconstituents.Besidesthepsychoactivecannabinoids,othercannabinoidssuchascannabinol (3), cannabidiol (4),andcannabigerol(7)alsoexhibitavarietyofpharmacologicaleffects(Izzo,Borrelli,Capasso,DiMarzo,&Mechoulam,2009).notably,cannabidiol(4)andcannabigerol(7)arenotpsychotropicbecauseoftheirinabilitytointeractwithcannabinoidCB1receptorsinthebrain(Izzoetal.,2009).

Consumption of Cannabis can lead to a varietyof behavioral effects such as sedation, impairment

FIGURE 58.1 Chemical structures of main phytocannabinoids isolated from Cannabis sativa L.

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ofshort-termmemory,motor incoordination;moodal-ternations that include euphoria, calmness, anxiety, orparanoia.Becauseofthehighlylipophilicpropertiesofphytocannabinoids,earlyscientificinquiresonhowcan-nabisworksledtoahypothesisthatcannabinoidsmayelicittheirbiologicaleffectsthroughnonspecificperturb-ingthemembranelipids(lawrence&Gill,1975).How-ever, this concept was diminished by the discovery ofthefirstcannabinoidreceptorinthelate1980s.

CANNABINOID RECEPTORS: WHAT THEY ARE

Discovery of Cannabinoid Receptors

Although nonspecific action of cannabis was thoughtto be possible, a series of pharmacological studies inlate 1980s indicated a receptor-mediated mechanismof action (Howlett & Fleming, 1984; Howlett, Qualy, &Khachatrian, 1986; little, Compton, Johnson, Melvin, &Martin,1988).ThefirstevidencefortheexistenceofabraintypecannabinoidreceptorcamefromdemonstrationofthespecificbindingsitesofsyntheticcannabimimeticsinratbrainP2membranesandsynaptosomes(Devane,Dysarz,Johnson,Melvin,&Howlett,1988).Thislandmarkfindingwasfollowedbytheconfirmationofcannabinoid-specificbinding sites in the brains of several other mammalianspecies, including human (Herkenham et al., 1990). Theconclusiveprooffortheexistenceofacannabinoidrecep-torwasprovidedbycloningandexpressionofacomple-mentaryDnA(cDnA),SKr6, fromaratcerebralcortexcDnA library (Matsuda, lolait, Brownstein, young, &Bonner,1990).TheproteinproductofSKr6differedsig-nificantly fromanyotherknownreceptor inaminoacidsequence,andshowshighselectivityforbindingtophyto-cannabinoidsandcannabimimeticagents.Becausethedis-tributionofitsmrnAmatchedwellwiththebindingsitesofcannabimimeticsinthebrain,thisreceptorwasnamedascannabinoidreceptor, formalizedlaterascannabinoidreceptortype1(CB1).SoonaftertheidentificationofCB1receptor,homologycloningdisclosedanotherformofcan-nabinoidreceptorfromthehumanpromyelocyticcelllineHl60 (Munro, Thomas, &Abu-Shaar, 1993). Because itsmrnAcouldnotbedetectedinthecentralnervoussys-temduringtheinitialcharacterizations,thisreceptorwasfirstly recognized as a peripheral cannabinoid receptor,andlaterwasformallydesignatedascannabinoidreceptortype2(CB2).FollowingthecloningofhumanCB2,therat(Griffin,Tao,&Abood,2000)andmouse(Shireetal.,1996),CB2 receptors were disclosed. Unlike the CB1 receptorwhich exhibits high amino acid identity across human,rat,andmouse(>97%)(Abood,Ditto,noel,Showalter,&Tao,1997;Gerard,Mollereau,Vassart,&Parmentier,1991),theCB2 receptordisplaysonly81%aminoacid identity

betweenhumanandrat,and82%identitybetweenhumanand mouse, respectively. notably, the sequences of hu-man,rat,andmouseCB2receptorsmarkedlydifferattheC-terminus.ThemouseCB2isshorterby13aminoacids;theratCB2is50aminoacidslongerthanthehumanCB2(Console-Bram,Marcu,&Abood,2012).

Endogenous Ligands of Cannabinoid Receptors

ThecloningofCB1andCB2receptorsmotivatednu-merous efforts to pursue the endogenous ligands thatcanactivatethecannabinoidreceptors.Itwasthendem-onstrated that mammalian tissues do synthesize andrelease lipid-derived molecules that can activate canna-binoid receptors and generate pharmacological effectssimilar to those from ∆9-THC (Di Marzo, De Petrocellis,& Bisogno, 2005; Hanuš, 2009; Martin, Mechoulam, &razdan, 1999). The first identified endogenous cannabi-noid, N-arachidonoylethanolamine (anandamide), wasisolatedfromporcinebrainin1992(Hanuš,2009).Itsiden-tityasanendogenouscannabinoidwasprovenbymanyin vitro and in vivo studies (Felder et al., 1996; Martinetal.,1999).later,another lipidderivative,2-arachidon-oylglycerol (2-AG) isolated from canine gut was showntobeapotentendogenouscannabinoid,andbindstotheCB1andCB2receptorsmoredevotedlythananandamide(Martinetal.,1999).Inthebrain,theconcentrationof2-AGisabout50–500-foldhigherthantheconcentrationofanan-damide.Additionally,2-AGbehavesasafullagonistfortheCB1andCB2receptors,whereasanandamideisapar-tialagonistatbothreceptors(DiMarzoetal.,2005).Thedegradationofanandamideisprimarilycatalyzedbyfattyacidamidehydrolase(FAAH),while2-AGismainlyme-tabolizedbymonoacylglycerollipase(MAGl)(DiMarzoetal.,2005).othercompoundsthathavebeenshownasendocannabinoidsincludenoladinether,N-arachidonoyl-dopamine, N-docasatetraenoylethanolamide, dihomo-γ-linolenoylethanolamide, o-arachidonoyl-ethanolamine(virodhamine), and meadethanolamide (Di Marzoetal.,2005;Hanuš,2009;Martinetal.,1999).ThestructuresoftheseendocannabinoidsarepresentedinFig.58.2.Theidentification of endogenous ligands completed the dis-coveryofcannabinoidCB1andCB2receptors.

The Structural Characteristics of CB1 and CB2 Receptors

TheCB1receptorisaproteinencodedbyCnr1genelocatedonhumanchromosome6,whereastheCB2re-ceptor is encoded by Cnr2 gene located on chromo-some1(yao&Mackie,2009).ExpressionsofthehumanCnr1andCnr2genes,respectively,provideaproteinwith472aminoacids(CB1),andaproteinwith360ami-no acids (CB2). The primary structures of human CB1andCB2receptorsareillustratedinFig.58.3.

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FIGURE 58.2 Chemical structures of known endocannabinoids.

FIGURE 58.3 Primary structures of CB1 and CB2 receptors. The amino acid sequence of thehuman CB1 (top panel) and CB2 (lower panel)receptors.ThehumanCB1receptorcomprisesof472aminoacids,whereasthehumanCB2receptorcontains 360 amino acids. The individual aminoacid is presented by one letter abbreviation. Theregionsshownwithred lettersaretransmembranedomains. The length and sequence homology ofthe third intracellular loop (regions representedwithblue characters)andtheC-terminals(regionsrepresentedwithgreen characters)ofthetworecep-torsubtypesarenotablydifferent.Theproteinse-quencesanddomainassignmentswereretrievedfrom the freelyaccessibleprotein-sequencedata-baseUniprot(http://www.uniprot.org).

http://www.uniprot.org/

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The two cannabinoid receptors belong to the largestfamily of receptors, which couple to guanine-nucleo-tide-binding proteins (G-proteins) at their intracellularsites. They share the structural characteristics of all G-protein-coupled receptors (GPCrs), possessing sevenhydrophobicdomains that transpass thecellmembraneseven times, forming helix bundles when embedded incell membrane. The seven transmembrane domains arelinkedbythreeextracellularandthreeintracellularloops,an extracellular n-terminal, and an intracellular C-ter-minal(Fig.58.3).Structurally,theCB1andCB2receptorsdistinguish themselves frommanyotherGPCrs in twoaspects(Matsuda,1997).UnlikemanyotherGPCrs,bothCB1andCB2receptorsdonotcontainconservedcyste-ineresidueswithinthesecondextracellulardomain(el1),whereasthethirdextracellulardomain(el2)containstwoormorecysteines.TheconservedcysteineresiduesinthesecondandthirdextracellulardomainsofGPCrsappeartostabilizethetertiarystructureofthereceptorthroughtheformationofintramoleculardisulfidelinkagewiththeneighboring transmembrane domains (TMs). Addition-ally,bothCB1andCB2 lackahighlyconservedprolineresidue in the fifth transmembrane (TM5) domain, bywhich a structural kink could be formed usually in thehelix(Matsuda,1997).IncomparisonwiththeCB2recep-tor,theCB1receptorhasanadditional72aminoacidresi-duesinthen-terminalsegment,15additionalresiduesinthethirdintracellularloop,and13additionalresiduesintheC-terminalregion(Figs.58.3and58.4).Thesequencehomology between the two cannabinoid receptors is44% in the full-length protein, and ranges from 33% to

82%withintheseventransmembraneregions(Fig.58.4).ThehighesthomologybetweenCB1andCB2isfoundinthetransmembraneTM2,TM3,TM6,andTM7domains(TM1:50%;TM2:66%;TM3:80%;TM4:33%;TM5:40%;TM6:60%;andTM7:82%)(Matsuda,1997).TheprimarystructuresofCB1andCB2receptorsshowthatthelengthand sequence homology of the third intracellular loopsand the C-terminals of the two receptors are consider-ablydifferent.Thesevariationsmightaffecttheircellularresponse to a ligand, because these regions are knownto mediate G-protein signal transduction (Howlett &Shim,2004),aswellasreceptordesensitizationandinter-nalization(Hsieh,Brown,Derleth,&Mackie,1999).

Atpresent,X-raycrystallographicstructuresofcanna-binoidreceptorsremainunknown.Intheabsenceofcrys-tallographicstructuresforCB1andCB2receptors,compu-tationalhomologymodelsofhumanCB1receptor(Shim,Welsh,&Howlett,2003)andhumanCB2receptor(raitio,Salo, nevalainen, Poso, & Jarvinen, 2005; Xie, Chen, &Billings,2003)havebeen respectivelyconstructedusingbovinerhodopsinastheprototypeofGPCrs.Site-directedmutation and computer-modeling have been employedtoidentifythekeyaminoacids(ormotif)involvedinli-gandbindingandreceptoractivation/deactivation.no-tableresidues identifiedincludelys192ofCB1receptor(Song&Bonner,1996)andSer112/T116ofCB2receptor(Taoetal.,1999),whichareinstrumentalforthebindingofmostcannabinoidligands.Thefunctionalresidues/motifinvolvedinligandbindingtotheCB1/CB2receptorhasbeen thoroughly reviewed (ortega-Gutierrez & lopez-rodriguez,2005).

FIGURE 58.4 Schematic representation of the cannabinoid CB1 and CB2 receptors.ThebluemodelrepresentsCB1receptorandthegreenmodelrepresentstheCB2receptor.TM,transmembrane;el,extracellularloop;il,intracellularloop.TheCB1receptorisalargerprotein,andhasadditional72aminoacidresiduesinthen-terminalsegment,13additionalresiduesinthethirdintracellularloop,and14additionalresiduesintheC-terminalregion.

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THE CANNABINOID RECEPTORS: WHERE THEY ARE

The cannabinoid receptors are widely distributedin the human body. CB1 is expressed primarily in thecentralnervoussystem(CnS),andisthemostabundantG-protein-coupled receptor in the brain (Mackie, 2005).Quantitative autoradiography revealed that the concen-trationofCB1receptors inbrain iscomparable to thoseofcorticalbenzodiazepinereceptor,striataldopaminere-ceptor,andwhole-brainglutamatereceptor(Herkenhametal.,1990).ThehighestdensityofCB1receptorsisfoundinthebasalganglia,particularlyinputamen,whichisin-volvedinmotorcontrol.HighlevelsofCB1receptorsarealsodetected incerebellum,hippocampus,andcerebralcortex.Thesebrainregionsareinvolvedincoordinatingbodymovements,learningandmemory,andhighercogni-tivefunctions,respectively(Mackie,2005;Pertwee,1997).ModeratelevelsofCB1receptorswerealsofoundinthebrainstem,spinalcord,hypothalamus,amygdala,centralgray, and nucleus of the solitary tract (Pertwee, 1997).BesidestheirpresenceinCnS,CB1receptorshavebeenfound in periphery, but at much lower level comparedtoitsbrainlevel.SomeimmunocytochemicalanalysesofCB1mrnAindicatedthepresenceofCB1receptor inavarietyofperipheraltissues/organs,includingliver,pan-creas,testis,fat,skeletalmuscle,retina,sperms,peripheralneurons,adrenalgland,heart,lung,prostate,uterus,ova-ry,bonemarrow,spleen,thymus,andtonsils(Bouaboulaet al., 1993; Galiegue et al., 1995; Pertwee, 1997; rice,Shannon,Burton,&Fiedeldey,1997).

EarlyinvestigationsofthemrnAofCB2receptorinthecerebraltissuesledtotheinferencethatCB2receptorisab-sentinthecentralnervoussystem,andpredominantlyex-pressedinthetissues/organsoftheimmunesystem,suchasspleen,tonsil,thymus,andlymphoidtissues(Galiegueetal.,1995;Munroetal.,1993;Schatz,lee,Condie,Pulaski,&Kaminski,1997).oftheseperipheralsites,tonsilsexhibitthehighestCB2mrnAlevel,whichisevenhigherthanthetotalconcentrationofCB1mrnAinthebrain(Galiegueetal.,1995).QuantitativeanalysisofCB2mrnArevealsthatmoderatetolowlevelsofCB2receptorscanbefoundin pancreas, bone marrow, uterus, and lung. likewise,highconcentrationsofCB2receptorscanbeidentifiedinhuman leukocytes such as B-cells, nK-cells, monocytespolymorphonuclear neutrophils, CD8+-T-lymphocytesandCD4+-T-lymphocytes(Bouaboulaetal.,1993;Galiegueetal.,1995).AlthoughearlyinvestigationsofCB2receptordidnotdetectthisreceptorinthebrain,VanSickleetal.(2005) have demonstrated that functional CB2 receptorsdo exist in the central nervous system, albeit in muchlowerconcentrationthanintheperiphery.SeveralrecentreportsalsodisclosedtheCB2immunoreactivityinmanybrainareas,suchasthehippocampalformation,olfactorybulb, cortex,midbrain,and thalamus (Gongetal., 2006;

onaivietal.,2006,2008a,b).Theseresultssupportthecon-clusionthatCB2receptorisnotanexclusivelyperipheralcannabinoid receptor. Additionally, CB2 receptors showaninduciblenatureundercertaindiseaseconditions.Forexample,microglialcellsinhealthybraindonotappeartoexpressCB2.However,inneurodegenerativedisordersas-sociatedwiththeactivationofbrainmicroglialcells,suchasAlzheimerandHuntingtondiseases,theexpressionofCB2 receptors in the brain can be significantly elevated(Benitoetal.,2003;Palazuelosetal.,2009).ThemultifocalexpressionsofCB2receptorsinthebrainsuggestthatCB2receptors may play broader roles in the central nervoussystemthanpreviouslypostulated.

CANNABINOID RECEPTORS: WHAT THEY DO

Thecannabinoidreceptorsaspartoftheendocannabi-noidsystemhavebeenshowntoplayimportantrolesinavarietyofphysiologicalconditions,includingneuronaldevelopment,neuronalplasticity,foodintakeandenergybalance, perception process, immune modulation, cellapoptosis, cardiovascular and reproductive functions(Marzo,Bifulco,&DePetrocellis,2004;rodriguezdeFon-secaetal.,2005).Themultifacetedfunctionsofcannabi-noidreceptorsarerootedbytheircellularphysiologyandcomplexsignalingpathwaysintransducingthebindingofcannabinoidligandsintobiologicalresponses.

Cell Physiology of Cannabinoid Receptors

Manystudieshavedemonstrated thatendocannabi-noidsfunctionasretrogrademessengersintheCnS.Theyare released from postsynaptic neurons in a calcium-dependent manner, and traverse retrogradely ontopresynaptic cannabinoid CB1 receptors. Subsequently,they produce a transient or prolonged reduction inthe release of neurotransmitters such as the inhibitoryγ-aminobutyricacid(GABA),excitatoryglutamate,acetyl-choline,andnoradrenaline(Piomelli,2003;rodriguezdeFonsecaetal.,2005).Unlikeclassicalpeptideneurotrans-mitters, endocannabinoids are not presynthesized andstored in vesicles before release. In contrast, they aresynthesized“ondemand,”viaenzymaticpathwaystrig-geredbyarapidincreaseofintracellularcalciumthroughcelldepolarizationorreceptoractivation.Atpresent,theknowledgeconcerningthephysiologyofCB2receptorsis relatively less than that of CB1 receptors. Given thehighlevelofCB2receptorsonthecellsofimmuneandhematopoieticsystems,CB2receptorsaremostlikelyin-volvedininflammation-associatedpathologies.Ingeneral,CB2receptorsareinvolvedinregulationofimmunecellsinseveralways,including:(1)inducingimmunecellapop-tosis,(2)suppressingproliferationofimmunecellsandthe

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production of proinflammatory cytokines/chemokines,(3)increasingsecretionofantiinflammatorycytokines,(4)inducingregulatoryTcells,and(5)promotingthetraffick-ingandmigrationofimmunecells(Klein&Cabral,2006;rom&Persidsky,2013).

Signal Transductions of CB1 and CB2 Receptors

Cannabinoidreceptorstransducesignalsthroughvari-ouspathways:G-protein-dependentprocesses (Demuth& Molleman, 2006; Pertwee, 1997) and G-protein-independentprocesses (Turu&Hunyady,2010;Velascoetal.,2005).ThemajorsignaltransductionsofbothCB1and CB2 receptors are primarily mediated through theinhibitory Gi and Go proteins. However, under certainconditions,signaltransductionsofCB1receptorthroughGq/11 and stimulatory Gs are also possible (Turu &Hunyady,2010).IncontrasttoCB1receptors,CB2receptorsdonottransducesignalsthroughstimulatoryGs(Demuth&Molleman,2006).Uponstimulationbyagonists, can-nabinoidreceptorsmodulateadenylylcyclaseand,conse-quently,alterthecellularproductionofcAMP.Althoughactivationofcannabinoidreceptorstypicallysuppressesadenylylcyclaseanddownregulatessignalingresponsesmediated by second messenger cAMP, evidence sug-gests that the isoformsofadenylylcyclaseexpressed incellsdeterminetheoutcomeofcAMPproduction.Forin-stance,inCoS-7cellsthatcoexpressCB1/CB2withnineisoformsofadenylylcyclase1to9,activationofthecan-nabinoidreceptorsCB1andCB2inhibitedtheactivityofadenylylcyclaseisoforms1,3,5,6,and8.Incontrast,ad-enylylcyclaseisozymes2,4,and7werestimulated(rhee,Bayewitch,Avidor-reiss, levy, & Vogel, 1998). In addi-tion, theCB1andCB2 receptors cancarry signal trans-ductionsthroughtheactivationofphosphatidylinositide3-kinases(PI3K),butwithdifferentmechanisms(Demuth&Molleman,2006;Howlett&Shim,2004).BoththeCB1andCB2cannabinoidreceptorsregulatethephosphory-lation and activation of different members of all threefamilies of mitogen-activated protein kinases (MAPKs),including p44/42 MAP kinase, p38 kinase, and JUn-terminalkinase (Atwood&Mackie,2010;Turu&Hun-yady,2010).UnliketheactivationofCB2receptor,whichgenerallyhasnoeffectonionchannels,activationofCB1receptor inhibits n- and P/Q-type voltage-gated Ca2+channels and activates A-type and G-protein-coupledinwardly-rectifyingK+channels(GIrK)(Howlett,2005).AlongwiththeG-proteinmediatedsignaltransductions,theCB1receptorcaninteractwithavarietyofnon-Gpro-teinpartners(eg,β-arrestins,adaptorproteinAP-3,GP-Cr-associatedsortingprotein1(GASP1),andtheadaptorproteinFAn)tocontrolreceptorsignalingortrafficking(Howlett, Blume, & Dalton, 2010; Smith, Sim-Selley, &Selley,2010).TheCB1andCB2cannabinoidreceptorscanalso transduce signals through G-protein independent

pathwaysthatemployceramideasthesecondmessenger(Velascoetal.,2005).Activationofcannabinoidreceptorsimpactsboththeshort-termandlong-termceramideac-cumulation, which is respectively resulted from sphin-gomylinhydrolysisandceramidedenovosynthesis.Ce-ramide,inturn,mediatescannabinoid-inducedmetabolicregulationandcellapoptosis(Herreraetal.,2006;Velascoetal.,2005).ThemajorsignalingpathwaysoftheCB1andCB2receptorsaresummarizedinFig.58.5.

The signaling events of CB1 and CB2 receptors canbe attenuated by desensitization of the receptor, fol-lowedbyan internalizationprocess (Atwood,Straiker,& Mackie, 2012). Desensitization involves G-protein-receptor-kinase-mediated phosphorylation of multipleserine/threonineresiduesofthereceptors,followedbybindingoftheβ-arrestins.Theinternalizedreceptorscanbe either transported to endosomes for dephosphory-lation,and then returned to thecellmembrane for thenext signaling event, or transported to lysosomes fordegradation. Apart from the agonist-initiated signaltransductions,bothCB1andCB2receptorscan inducecellular responses through constitutive activities (socalled “constitutive tone”). In the absence of agonists,thetwocannabinoidreceptorshavebeenshowntoex-hibit a spontaneous activation of Gi/o-proteins, and in-creased constitutive MAPK-activating properties (yao&Mackie,2009).Theseconstitutiveactivitiescanbere-spectivelyattenuatedbyinverseagoniststhatcanselec-tivelyinteractwiththeCB1andCB2receptors.

CONCLUDING REMARKS

Theisolationof∆9-THCfromcannabis,theidentifica-tion and cloning of the two cannabinoid receptors, andthediscoveryofendogenousCBligands,revealedtheex-istenceoftheendocannabinoidsystem.Inthepastthreedecades,investigationofthemolecularbiologyandphar-macologyoftheendocannabinoidsystemhasimplicateditsimportanceinalargenumberofphysiologicalfunctionsinhuman.Modulatingthefunctionsof thecannabinoidreceptors, either directly or indirectly, holds therapeuticpromisesforamelioratinganumberofpathologicalcon-ditions, ranging from the diseases of nervous systems,suchaspsychiatricdisorders,ParkinsonandHuntingtondisease,multiplesclerosisandspinalcordandbrainin-juries,topain,inflammation,andcancer,aswellassomecardiovascular and metabolic disorders including ath-erosclerosis,myocardial infarction,hypertension,stroke,obesity/metabolic syndrome, and osteoporosis, amongothers (Pacher, Bátkai, & Kunos, 2006). Further under-standingthemolecularbiologyandpharmacologyofthecannabinoidreceptorswillcreatemoreopportunitiesforthediscoveryofnovelandsafermedicationsbytargetingofcannabinoidreceptorsmoreselectively.

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Cannabinoid receptors CannabinoidreceptorsaretheG-protein-coupledreceptorsthatmediatethebiologicaleffectsofphytocannabinoids,endocannabinoids,andsyntheticcannabimimeticcompounds.Cannabinoids Cannabinoidsareagroupofbiologicallyactivecompoundsisolatedfromtheplantcannabis,andareoftenreferredtoasphytocannabinoids,someofwhichareresponsibleforthepsychoactiveeffectsofcannabis.Endocannabinoids Endocannabinoidsarethemoleculesproducedbyhumanandanimalswhichexhibitsimilarbiologicalactivitiesasphytocannabinoids.G-protein-coupled receptors G-protein-coupledreceptors(GPCrs)aremembrane-boundsignaltransductionproteinsthatassociatewithguanosinenucleotide-bindingproteins(G-proteins)ontheirintracellularside.Uponbindingtocertaintypeofchemicalcompounds,theGPCrschangeshapes,andcausethedisassemblyoftheassociatedG-proteinsintosubunits,whichfurthertransducethesignaltothedownstreamproteinsandeventuallyleadtocellularresponses.

Synthetic cannabimimetics Chemicalcompoundssynthesizedinlaboratoriesthatexhibitsimilarbiologicalactivitiesasphytocannabinoids.

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FIGURE 58.5 Major signaling pathways initiated from activation of the cannabinoid CB1 and CB2 receptors.Themajorsignalingpathwaysinitiatedbythebindingofagonists(ECB)tocannabinoidreceptorsinvolvetheactivationanddissociationofthecoupledGi/o-proteinheterotrimers(ie,αandβγsubunits).ThereleasedGαsubunitsinteractwithadenylylcyclase(AC)andinhibititsactivityinsynthesisofcAMP.ThisdecreasestheactivationofproteinkinaseA(PKA),whichinturndownregulatesPKA-mediatedsignalingevents.Theβγsubunitscanevokethephosphati-dylinositide3-kinase(PI3K)andproteinkinaseB(PKB)pathways,whichinturninducethephosphorylationofP42/44MAPKandothermembersofMAPKsuchasJnKandp38MAPK.TheCB1andCB2receptorscanalsocoupletonon-G-proteinpartnerssuchasFAn,whichactivatesneutralsphingomyelinase(SMase)thatmediatesthegenerationofceramidefromsphingomyelin.Whileceramideisinvolvedinotherfunctions,itcanfunctionasasecondmessengertoactivateseveraldownstreameffectors,includingErK,JnK,andp38thatarefurtherinvolvedinthecontrolofgenetranscriptionsandcellfate.ActivationofCB1receptorinhibitsnandP/Qtypesofvoltagegatedcalciumchannels(VGCC),whilepositivelyregulatesA-typeK+(KA),andinwardlyrectifyingK+(Kir)channels.ThemodulationsofionchannelsbyCB1areindependentofthecAMPpathway,andareinvolvedintheregulationofneurotransmitterrelease.Incontrast,activationofCB2receptorsgenerallydoesnotregulateionchannels.

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V. PHArMAColoGyAnDCEllUlArACTIVITIESoFCAnnABInoIDSAnDEnDoCAnnABInoIDS

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Chapter 58 - Cannabinoids and the Cannabinoid Receptors: An OverviewList of AbbreviationsIntroductionCannabis and cannabinoidsCannabinoid receptors: what they areDiscovery of Cannabinoid ReceptorsEndogenous Ligands of Cannabinoid ReceptorsThe Structural Characteristics of CB1 and CB2 Receptors

The cannabinoid receptors: where they areCannabinoid receptors: what they doCell Physiology of Cannabinoid ReceptorsSignal Transductions of CB1 and CB2 Receptors

Concluding remarksMini-dictionaryReferences