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Cannabinoid Receptors: an Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

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Cannabinoid Receptors: an Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases International Journal of Molecular Sciences Review Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases Dhanush Haspula 1 and Michelle A. Clark 2,* 1 Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA; [email protected] 2 Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33314, USA * Correspondence: [email protected] Received: 26 September 2020; Accepted: 15 October 2020; Published: 17 October 2020 Abstract: The identification of the human cannabinoid receptors and their roles in health and disease, has been one of the most significant biochemical and pharmacological advancements to have occurred in the past few decades. In spite of the major strides made in furthering endocannabinoid research, therapeutic exploitation of the endocannabinoid system has often been a challenging task. An impaired endocannabinoid tone often manifests as changes in expression and/or functions of type 1 and/or type 2 cannabinoid receptors. It becomes important to understand how alterations in cannabinoid receptor cellular signaling can lead to disruptions in major physiological and biological functions, as they are often associated with the pathogenesis of several neurological, cardiovascular, metabolic, and inflammatory diseases. This review focusses mostly on the pathophysiological roles of type 1 and type 2 cannabinoid receptors, and it attempts to integrate both cellular and physiological functions of the cannabinoid receptors. Apart from an updated review of pre-clinical and clinical studies, the adequacy/inadequacy of cannabinoid-based therapeutics in various pathological conditions is also highlighted. Finally, alternative strategies to modulate endocannabinoid tone, and future directions are also emphasized. Keywords: endocannabinoid system; neurological diseases; cardiac functions; metabolic diseases; immune functions 1. Introduction Discovery of the Endocannabinoid System The therapeutic potential of cannabis, commonly known as marijuana, has been a subject of great interest for several centuries. Its anxiolytic and euphoric properties were acknowledged in religious scriptures that date back to several millennia [1]. Many cultures and civilizations have used cannabis preparations to treat a variety of ailments, ranging from rheumatism, inflammation and malaria for several millennia [2]. While evidence of therapeutic utility of cannabis was known in Asia and Africa, cannabis was relatively unknown to the western world until the 19th century [3]. The first scientific report on cannabis was published by the Irish physician, William ‘O Shaughnessy, which marked the earliest traces of cannabis globalization. By providing evidence of its therapeutic efficacy and safety for pathological conditions such as infantile convulsions and cholera, he was instrumental in laying the foundation for cannabis research [3]. Pioneering works from the groups Int. J. Mol. Sci. 2020, 21, 7693; doi:10.3390/ijms21207693 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 7693 2 of 61 of Todd, Adams, and Mechoulam, in the 20th century, led to a better understanding of the chemical makeup of cannabis [4–7]. The first report of the existence of the brain cannabinoid receptor, termed the cannabinoid receptor type 1 (CB1R), was reported by Howlett’s group in the late 1980s [8]. The discovery of the CB1R was followed by the identification of the second cannabinoid receptor, termed the peripheral cannabinoid receptor (due to the lack of expression in brain) or cannabinoid receptor type 2 (CB2R) by Abu-Shaar’s group [9], and their two endogenous ligands, anandamide and 2-arachidonoylglycerol (2-AG) [10–12], by Mechoulam’s and Waku’s groups. The identification of biosynthetic and degradative pathways of endocannabinoids in the following years, make up the classical endocannabinoid system [13–17]. These seminal discoveries laid the foundations for endocannabinoid research. For a detailed account on cannabinoid and endocannabinoid history, please refer to the excellent reviews by Di Marzo [3] and Pertwee [18]. 2. Cannabinoid Receptors 2.1. Molecular Architecture The CB1 gene (CNR1), which was first cloned by Matsuda et al. [19], encodes for the CB1R. The human CNR1 is located on chromosome 6 (6q15, HGNC:2159) [20], and comprises of four exons, with exon 4 described as the main coding exon [21,22]. The mouse and rat CNR1, localized on chromosome 4 and 5 respectively, comprises of a single promoter [23]. The CB1R, a 53 kDa protein, is glycosylated post-translationally resulting in a 64 kDa glycosylated form [24]. The glycosylated fraction supersedes the non-glycosylated fraction in abundance [24]. The CB1R belongs to the Class A G protein coupled receptor (GPCR) subfamily, often regarded as one the most diverse subfamilies of GPCRs in humans [25]. Similar to the other GPCRs in this family, the CB1R comprises of a seven-transmembrane helical domain, extracellular and intracellular loops, an extracellular N terminus and an intracellular carboxy terminal tail [25,26]. The extracellular N terminal region is an important factor in conferring receptor stability and trafficking [27,28]. Although the N-terminal region has been reported to have a minor role in orthosteric binding, the membrane-proximal region of the tail is implicated in the modulation of the binding affinity of allosteric ligands [27,29]. Published crystal structure studies of inverse agonist- and antagonist-bound CB1R further helped to characterize the ligand binding pocket and provided insight into the importance of the extracellular loop, the N-terminal region, and the specific transmembrane helices for docking of agonists [30,31]. Similar to the other GPCRs, the second and the third intracellular loops have been demonstrated to have an important role in both receptor activation and desensitization [32,33], while the carboxy terminal tail mostly regulates desensitization and internal sorting [34,35]. Phosphorylation of serine and threonine residues located in the carboxy terminal region has been shown to regulate receptor desensitization and internalization via interaction with the CB1R interacting protein (CR1P) 1a [36], G protein coupled receptor kinases [34] and arrestins [37]. Interestingly, the carboxy terminal region has also been reported to adopt two amphipathic helical domains, which are functionally capable of affecting receptor signaling, polarity and surface expression [38–41]. The CB2 gene (CNR2), which was first cloned by Munro et al. [9], encodes for the CB2R. The human CNR2 is located on chromosome 1 (1p36.11, HGNC ID: 2160). Unlike CNR1, both human and mouse CNR2 have been reported to comprise of two separate promoters [42]. The CB2R has a similar structure to the other GPCRs in this class. It comprises of 7 transmembrane domains, N terminus and C terminus, 3 extracellular and intracellular loops, and also an amphipathic cytoplasmic helix [43–45]. The CB2R shares 44% of overall sequence identity, and 68% of transmembrane sequence identity, although the sequence identity has been reported to be lower in TM1, TM4 and TM5 [9,46]. Unlike the CB1R, the CB2R does not have a long N-terminal region. Other key differences include an aromatic-rich environment in the TM5 of CB2R, and a lack of phosphorylation site for PKC in the third intracellular loop in CB2R, the latter of which is present in CB1R [46]. The second intracellular loop in combination with the carboxy terminal region plays a pivotal role in CB2R-mediated signal transduction [47]. Int. J. Mol. Sci. 2020, 21, 7693 3 of 61 2.2.Int. Ligands J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 66 2.2.1.2.2.1. Endogenous Endogenous Cannabinoids Cannabinoids BothBoth CB1Rs CB1Rs and and CB2Rs CB2Rs are classare class A, lipid-like A, lipid-like GPCRs GPCRs that are that activated are activated by endogenously by endogenously produced lipophilicproduced ligands lipophilic [48 ].ligands The prototypical [48]. The prototypical endogenous endogenous cannabinoids cannabinoids or endocannabinoids or endocannabinoids are 2-AG andare anandamide. 2-AG and anandamide. 2-AG and 2-AG anandamide and anandamide are eicosanoids are eicosanoids that are that synthesized are synthesized on-demand on-demand from arachidonicfrom arachidonic acid-containing acid-containing phospholipids, phospholipids, such as phosphatidylinositolsuch as phosphatidylinositol 4,5-bisphosphate 4,5-bisphosphate (PIP2) and phosphatidylethanolamine(PIP2) and phosphatidylethanolamine (PE), respectively. (PE), respectively. These ligands These have ligands complementary have complementary as well as divergent as well functionsas divergent [49]. functions While 2-AG [49]. is While a full agonist2-AG is ata full both agonist CB1Rs at and both CB2Rs, CB1Rs anandamide and CB2Rs, isanandamide a partial agonist is a forpartial both receptors.agonist for Other both receptors. lesser-known Other endocannabinoids lesser-known endocannabinoids or non-classical or eicosanoids non-classical include, eicosanoids N-acyl dopamineinclude, N-acyl (NADA) dopamine and 2-arachidonyl (NADA) and glyceryl 2-arachidonyl ether (noladinglyceryl ether ether), (noladin both of ether), which both bind of stronglywhich tobind the CB1Rstrongly [50 to,51 the]. Additionally,CB1R [50,51]. Additionally, virodhamine viro wasdhamine identified was to identified
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