The CB1 Receptor as the Cornerstone of Exostasis
2017; Cell Press; Volume: 93; Issue: 6 Linguagem: Inglês
10.1016/j.neuron.2017.02.002
ISSN1097-4199
AutoresPier Vincenzo Piazza, Daniela Cota, Giovanni Marsicano,
Tópico(s)Dietary Effects on Health
ResumoThe type-1 cannabinoid receptor (CB1) is the main effector of the endocannabinoid system (ECS), which is involved in most brain and body functions. In this Perspective, we provide evidence indicating that CB1 receptor functions are key determinants of bodily coordinated exostatic processes. First, we will introduce the concepts of endostasis and exostasis as compensation or accumulation for immediate or future energy needs and discuss how exostasis has been necessary for the survival of species during evolution. Then, we will argue how different specific biological functions of the CB1 receptor in the body converge to provide physiological exostatic processes. Finally, we will introduce the concept of proactive evolution-induced diseases (PEIDs), which helps explain the seeming paradox that an evolutionary-selected physiological function can become the cause of epidemic pathological conditions, such as obesity. We propose here a possible unifying theory of CB1 receptor functions that can be tested by future experimental studies. The type-1 cannabinoid receptor (CB1) is the main effector of the endocannabinoid system (ECS), which is involved in most brain and body functions. In this Perspective, we provide evidence indicating that CB1 receptor functions are key determinants of bodily coordinated exostatic processes. First, we will introduce the concepts of endostasis and exostasis as compensation or accumulation for immediate or future energy needs and discuss how exostasis has been necessary for the survival of species during evolution. Then, we will argue how different specific biological functions of the CB1 receptor in the body converge to provide physiological exostatic processes. Finally, we will introduce the concept of proactive evolution-induced diseases (PEIDs), which helps explain the seeming paradox that an evolutionary-selected physiological function can become the cause of epidemic pathological conditions, such as obesity. We propose here a possible unifying theory of CB1 receptor functions that can be tested by future experimental studies. One of the most fascinating chapters in the physiology of multicellular organisms lies in the discovery and study over the last decades of the functions of the endocannabinoid system (ECS) and its main effector the cannabinoid type-1 receptor (CB1). Despite an intense accumulation of data, the diverse physiological roles of CB1 still constitute the pieces of a jigsaw puzzle that taken one by one give the impression of scattered and seemingly unrelated tissue-specific actions. CB1 was discovered as the target of the main psychotropic component of the plant Cannabis sativa (marijuana) Δ9-tetrahydrocannabinol (THC) (Howlett et al., 2002Howlett A.C. Barth F. Bonner T.I. Cabral G. Casellas P. Devane W.A. Felder C.C. Herkenham M. Mackie K. Martin B.R. et al.International Union of Pharmacology. XXVII. Classification of cannabinoid receptors.Pharmacol. Rev. 2002; 54: 161-202Crossref PubMed Scopus (1815) Google Scholar, Piomelli, 2003Piomelli D. The molecular logic of endocannabinoid signalling.Nat. Rev. Neurosci. 2003; 4: 873-884Crossref PubMed Scopus (1309) Google Scholar). Since the identification of THC (Adams, 1942Adams R. Marihuana: Harvey Lecture, February 19, 1942.Bull. N. Y. Acad. Med. 1942; 18: 705-730PubMed Google Scholar, Gaoni and Mechoulam, 1964Gaoni Y. Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish.J. Am. Chem. Soc. 1964; 86: 1646-1647Crossref Google Scholar) and the later characterization of cannabinoid receptors (Matsuda et al., 1990Matsuda L.A. Lolait S.J. Brownstein M.J. Young A.C. Bonner T.I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA.Nature. 1990; 346: 561-564Crossref PubMed Scopus (3503) Google Scholar), enormous progress has been made in understanding cannabinoid mechanisms of action and in identifying the physiological roles of cannabinoid receptors. Endogenous ligands for these receptors exist (endocannabinoids), which are mainly lipid compounds derived from arachidonic acid. Endocannabinoids, cannabinoid receptors, and the enzymatic machinery for endocannabinoid synthesis and degradation form the endocannabinoid system (ECS). The functions of the ECS are difficult to enumerate because almost all body processes can involve endocannabinoid signaling in physiological or pathological conditions. Due to this huge diversity, these functions have been addressed separately, suggesting that multiple forms of evolutionary pressure contributed to the development of the ECS to fulfill different and unrelated functions. In this Perspective, we argue that this might not be the case. We propose that the main function of the ECS, and in particular of CB1 receptors, is to promote exostatic processes in the regulation of body energy balance. Energy homeostasis is provided by two evolutionarily conserved processes: endostasis, which is aimed at fulfilling immediate energetic needs, and exostasis, aimed at promoting the accumulation of energetic stores for future needs. Most of CB1 receptor functions largely fulfill the requirements for a prototypical exostatic system, providing a novel unified perspective for future studies. In this section, we will introduce the concepts of endostasis and exostasis, key physiological processes selected during evolution to guarantee individual and species survival. Most animals when exposed to ad libitum access to food, especially palatable and attractive foods, will eventually over-eat and become overweight and obese (Bernstein et al., 1975Bernstein I.L. Lotter E.C. Kulkosky P.J. Porte Jr., D. Woods S.C. Effect of force-feeding upon basal insulin levels of rats.Proc. Soc. Exp. Biol. Med. 1975; 150: 546-548Crossref PubMed Google Scholar). Obesity is a pathological state with the potential to reduce the chance of survival, making this over consumption behavior paradoxically self-damaging. This observation indicates that the motivational and metabolic processes regulating food intake and energy balance can go beyond the immediate energetic needs of subjects. This apparent paradox is difficult to understand without taking into account the evolutionary constraints that contributed to the development of the systems that regulate energy balance. It is well established that energy balance defined here as the balance between the intake and the use of energy by the organism is regulated by two major systems classically called the homeostatic or compensated system (Berthoud, 2003Berthoud H.R. Neural systems controlling food intake and energy balance in the modern world.Curr. Opin. Clin. Nutr. Metab. Care. 2003; 6: 615-620Crossref PubMed Scopus (0) Google Scholar, de Castro and Plunkett, 2002de Castro J.M. Plunkett S. A general model of intake regulation.Neurosci. Biobehav. Rev. 2002; 26: 581-595Crossref PubMed Scopus (0) Google Scholar) and the non-homeostatic or uncompensated system (Berthoud, 2003Berthoud H.R. Neural systems controlling food intake and energy balance in the modern world.Curr. Opin. Clin. Nutr. Metab. Care. 2003; 6: 615-620Crossref PubMed Scopus (0) Google Scholar, de Castro and Plunkett, 2002de Castro J.M. Plunkett S. A general model of intake regulation.Neurosci. Biobehav. Rev. 2002; 26: 581-595Crossref PubMed Scopus (0) Google Scholar). The compensated or homeostatic system responds to a decrease in the internal energy status of the organism by eliciting hunger and food intake. This system is motivationally controlled by an internal drive, a decrease in available energy levels, and sub-serves the function of coping with the immediate need of the organism (Berthoud, 2003Berthoud H.R. Neural systems controlling food intake and energy balance in the modern world.Curr. Opin. Clin. Nutr. Metab. Care. 2003; 6: 615-620Crossref PubMed Scopus (0) Google Scholar, de Castro and Plunkett, 2002de Castro J.M. Plunkett S. A general model of intake regulation.Neurosci. Biobehav. Rev. 2002; 26: 581-595Crossref PubMed Scopus (0) Google Scholar). The adjectives homeostatic or compensated were used because eating and the related signals of replenished energy (nutrients, hormones) generally induce an inhibition of food intake in order to avoid overeating and metabolic overload (Berthoud, 2003Berthoud H.R. Neural systems controlling food intake and energy balance in the modern world.Curr. Opin. Clin. Nutr. Metab. Care. 2003; 6: 615-620Crossref PubMed Scopus (0) Google Scholar, Berthoud, 2011Berthoud H.R. Metabolic and hedonic drives in the neural control of appetite: who is the boss?.Curr. Opin. Neurobiol. 2011; 21: 888-896Crossref PubMed Scopus (190) Google Scholar, de Castro and Plunkett, 2002de Castro J.M. Plunkett S. A general model of intake regulation.Neurosci. Biobehav. Rev. 2002; 26: 581-595Crossref PubMed Scopus (0) Google Scholar). In contrast, non-homeostatic or uncompensated mechanisms are activated by the presence of food in the environment (Berthoud, 2003Berthoud H.R. Neural systems controlling food intake and energy balance in the modern world.Curr. Opin. Clin. Nutr. Metab. Care. 2003; 6: 615-620Crossref PubMed Scopus (0) Google Scholar, Berthoud, 2011Berthoud H.R. Metabolic and hedonic drives in the neural control of appetite: who is the boss?.Curr. Opin. Neurobiol. 2011; 21: 888-896Crossref PubMed Scopus (190) Google Scholar, de Castro and Plunkett, 2002de Castro J.M. Plunkett S. A general model of intake regulation.Neurosci. Biobehav. Rev. 2002; 26: 581-595Crossref PubMed Scopus (0) Google Scholar). The presence, detection, and specific organoleptic characteristics of food act as triggers to stimulate food intake. Whereas hunger is generally considered the only motivational drive to ingest food, we often eat simply because food is available. In this case, the incentive properties of food (i.e., its presence, organoleptic features, and palatability) represent the motivational force to eat (Berthoud, 2003Berthoud H.R. Neural systems controlling food intake and energy balance in the modern world.Curr. Opin. Clin. Nutr. Metab. Care. 2003; 6: 615-620Crossref PubMed Scopus (0) Google Scholar, Berthoud, 2011Berthoud H.R. Metabolic and hedonic drives in the neural control of appetite: who is the boss?.Curr. Opin. Neurobiol. 2011; 21: 888-896Crossref PubMed Scopus (190) Google Scholar, de Castro and Plunkett, 2002de Castro J.M. Plunkett S. A general model of intake regulation.Neurosci. Biobehav. Rev. 2002; 26: 581-595Crossref PubMed Scopus (0) Google Scholar). The presence of food, especially if palatable and rich in calories, exerts a positive, motivational pull that seems independent from the immediate needs of the individual. This results in eating in an apparently unregulated fashion (Berthoud, 2003Berthoud H.R. Neural systems controlling food intake and energy balance in the modern world.Curr. Opin. Clin. Nutr. Metab. Care. 2003; 6: 615-620Crossref PubMed Scopus (0) Google Scholar, Berthoud, 2011Berthoud H.R. Metabolic and hedonic drives in the neural control of appetite: who is the boss?.Curr. Opin. Neurobiol. 2011; 21: 888-896Crossref PubMed Scopus (190) Google Scholar, de Castro and Plunkett, 2002de Castro J.M. Plunkett S. A general model of intake regulation.Neurosci. Biobehav. Rev. 2002; 26: 581-595Crossref PubMed Scopus (0) Google Scholar). The uncompensated mechanism of food intake is responsible for the reinstatement of food intake in sated animals that are presented with a new and/or more palatable food. This system is responsible for the higher amount of food ingested in circumstances where the diet is composed of several types of food with different organoleptic features (Berthoud, 2003Berthoud H.R. Neural systems controlling food intake and energy balance in the modern world.Curr. Opin. Clin. Nutr. Metab. Care. 2003; 6: 615-620Crossref PubMed Scopus (0) Google Scholar, Berthoud, 2011Berthoud H.R. Metabolic and hedonic drives in the neural control of appetite: who is the boss?.Curr. Opin. Neurobiol. 2011; 21: 888-896Crossref PubMed Scopus (190) Google Scholar, de Castro and Plunkett, 2002de Castro J.M. Plunkett S. A general model of intake regulation.Neurosci. Biobehav. Rev. 2002; 26: 581-595Crossref PubMed Scopus (0) Google Scholar). The uncompensated system is also responsible for the increase in food intake induced by the presence of congeners (Berthoud, 2003Berthoud H.R. Neural systems controlling food intake and energy balance in the modern world.Curr. Opin. Clin. Nutr. Metab. Care. 2003; 6: 615-620Crossref PubMed Scopus (0) Google Scholar, Berthoud, 2011Berthoud H.R. Metabolic and hedonic drives in the neural control of appetite: who is the boss?.Curr. Opin. Neurobiol. 2011; 21: 888-896Crossref PubMed Scopus (190) Google Scholar, de Castro and Plunkett, 2002de Castro J.M. Plunkett S. A general model of intake regulation.Neurosci. Biobehav. Rev. 2002; 26: 581-595Crossref PubMed Scopus (0) Google Scholar). These mechanisms can be illustrated in an anecdotic everyday-life example: imagine being at the end of a copious dinner with friends. Of course, you feel satiated. However, suddenly a fantastic dessert is brought to the table, which is the same one that your grandmother used to prepare for you when you were a kid. Sated or not, you will eat and probably have two or three helpings, likely with negative consequences on your metabolic profile (at least for the next few days). However, this behavior is perfectly normal, and it does not indicate psychological unbalance or lack of control. It is just a sign that in those moments you are experiencing the power of the major system controlling food intake. Indeed, not only personal experiences, but also mathematical models have shown that the influence on behavior of the uncompensated system is stronger and can overcome the compensated one (Berthoud, 2003Berthoud H.R. Neural systems controlling food intake and energy balance in the modern world.Curr. Opin. Clin. Nutr. Metab. Care. 2003; 6: 615-620Crossref PubMed Scopus (0) Google Scholar, Berthoud, 2011Berthoud H.R. Metabolic and hedonic drives in the neural control of appetite: who is the boss?.Curr. Opin. Neurobiol. 2011; 21: 888-896Crossref PubMed Scopus (190) Google Scholar, de Castro and Plunkett, 2002de Castro J.M. Plunkett S. A general model of intake regulation.Neurosci. Biobehav. Rev. 2002; 26: 581-595Crossref PubMed Scopus (0) Google Scholar). It is worth noting that the distinction between the different motivational forces is schematic in nature: drive and incentive can overlap in terms of both behavioral processes and cellular mechanisms. Incentive properties of food increase with hunger, and hormones associated with low energy status can increase the activity of incentive-related brain circuits such as the mesocorticolimbic circuitry that includes dopamine neurons of the ventral tegmental area (VTA). The stomach-derived hormone ghrelin, whose levels are high in fasting, increases impulsive behavior and drives binge eating by acting through VTA dopamine neurons (Anderberg et al., 2016Anderberg R.H. Hansson C. Fenander M. Richard J.E. Dickson S.L. Nissbrandt H. Bergquist F. Skibicka K.P. the stomach-derived hormone ghrelin increases impulsive behavior.Neuropsychopharmacology. 2016; 41: 1199-1209Crossref PubMed Scopus (4) Google Scholar, Valdivia et al., 2015Valdivia S. Cornejo M.P. Reynaldo M. De Francesco P.N. Perello M. Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling.Psychoneuroendocrinology. 2015; 60: 206-216Abstract Full Text Full Text PDF PubMed Google Scholar). Conversely, hormones that signal energy surfeit to the brain, such as leptin and insulin, decrease reactivity to cues associated with palatable foods and reduce food intake by inhibiting VTA dopamine neurons (Hommel et al., 2006Hommel J.D. Trinko R. Sears R.M. Georgescu D. Liu Z.W. Gao X.B. Thurmon J.J. Marinelli M. DiLeone R.J. Leptin receptor signaling in midbrain dopamine neurons regulates feeding.Neuron. 2006; 51: 801-810Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar, Khanh et al., 2014Khanh D.V. Choi Y.H. Moh S.H. Kinyua A.W. Kim K.W. Leptin and insulin signaling in dopaminergic neurons: relationship between energy balance and reward system.Front. Psychol. 2014; 5: 846Crossref PubMed Scopus (10) Google Scholar, Mebel et al., 2012Mebel D.M. Wong J.C. Dong Y.J. Borgland S.L. Insulin in the ventral tegmental area reduces hedonic feeding and suppresses dopamine concentration via increased reuptake.Eur. J. Neurosci. 2012; 36: 2336-2346Crossref PubMed Scopus (0) Google Scholar, van der Plasse et al., 2015van der Plasse G. van Zessen R. Luijendijk M.C. Erkan H. Stuber G.D. Ramakers G.M. Adan R.A. Modulation of cue-induced firing of ventral tegmental area dopamine neurons by leptin and ghrelin.Int. J. Obes. 2015; 39: 1742-1749Crossref Scopus (22) Google Scholar). Accordingly, hypothalamic circuits that are classically viewed as the target of the action of hormones involved in the regulation of feeding behavior (Berthoud, 2011Berthoud H.R. Metabolic and hedonic drives in the neural control of appetite: who is the boss?.Curr. Opin. Neurobiol. 2011; 21: 888-896Crossref PubMed Scopus (190) Google Scholar) can also be rapidly modulated by incentive stimuli (Chen et al., 2015Chen Y. Lin Y.C. Kuo T.W. Knight Z.A. Sensory detection of food rapidly modulates arcuate feeding circuits.Cell. 2015; 160: 829-841Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). Fasting-induced hyperphagia might represent an example of the overlap between different forces, where different mechanisms (e.g., endogenous drive to eat, inhibition of satiety signals, increased palatability of food, etc.) converge to increase the intake of energy. Nevertheless, the discrimination between compensated and uncompensated systems is valid and represents an optimal theoretical frame to understand the motivational mechanisms underlying food intake and energy accumulation. A question immediately arises from these observations: why do we have an uncompensated, non-homeostatic system whose consequence is to make us overweight and eventually more prone to develop diseases, such as cardiovascular disorders, diabetes, and cancer? How is it possible that such a system has survived evolutionary selection? The adaptive value of this system is quite difficult to understand in the present environmental conditions of developed western countries, where food availability is virtually unlimited. However, humans have been hunters and gatherers for approximately four million years (Harari, 2015Harari Y.N. Sapiens: A Brief History of Humankind. HarperCollins, 2015Google Scholar). Consequently, during the largest period of the evolution of our species, there was no direct control on food availability and our ability to store gathered or hunted food was extremely limited. In these variable foraging conditions, having a system that was able to overcome immediate needs and increase energy storage to cope with future foraging difficulties was clearly fundamental for survival (Figure 1). Sufficient calorie storage in the form of fat also favored reproduction. Individuals under a stronger control of "non-compensated" motivational forces acquired a clear advantage for the maintenance of the species. By definition, physiological mechanisms have all evolved to maintain survival of individuals and species. Thus, physiological processes have to be considered "homeostatic," as opposed to pathological ones, which are "non-homeostatic." In this sense, defining a biological and non-pathological process as "non-homeostatic" could appear as an oxymoron. Similarly, the term "uncompensated" recalls unbalanced conditions, which are difficult to conceptualize for physiological states and mechanisms. Conversely, we believe that both systems regulating energy balance are "homeostatic" and "compensated" in nature in the sense that both have been selected during evolution to maximize the chances of survival. We propose to rename the two systems described above to reflect the homeostatic control of energy balance. We prefer to think of the homeostatic or compensated system as endostatic and the non-homeostatic or uncompensated system as exostatic (Figure 2). The endostatic system ("I eat when hungry") has evolved to counteract a decrease in endogenous levels of energy and to allow individuals to cope with present energy needs. It is endostatic because motivational and metabolic processes respond mainly to endogenous signals of the organism. Conversely, the exostatic system ("I eat when food is available") has the role of compensating for potential decreases in the external levels of nutrients and allows individuals to cope with future needs. It is exostatic, because the stimuli triggering ingestion and accumulation of energy are external to the individual and involve innate and learned responses to food and associated stimuli (Figure 2). Both endostatic and exostatic mechanisms confer clear advantages to the adaptive possibilities of individuals in an environment with variable foraging conditions where food availability can rapidly change due to unforeseen events such as climatic perturbations or epidemics in a principal foraging source. Maintaining both endostatic and exostatic systems within a species confers a clear evolutionary advantage. Individuals with a stronger endostatic phenotype will have a greater chance of surviving periods of abundant food availability by avoiding over-eating and excessive accumulation of fat. These same individuals will be at a disadvantage during periods of paucity. Conversely, predominantly "exostatic" subjects will have a greater chance during periods of scarce energy sources but will be at risk of over-eating, obesity, and associated metabolic problems in conditions of abundance (Figure 2). The large availability of calorie-rich food that can be obtained with very limited energy expenditure (going to the fridge costs less energy than hunting in the forest) sets the physiological exostatic system as a danger for the health and wellbeing of individuals in Western, developed countries. We propose that CB1 receptor signaling in the body largely contributes to exostatic functions. In the following section, we will expand this idea by first describing the molecular organization of the ECS and then discussing how the large majority of CB1 receptor-dependent functions fit with the theoretical properties of an exostatic system. The ECS is comprised of the cannabinoid receptors CB1 and CB2, their endogenous ligands, the classical arachidonic acid-derivate lipid endocannabinoids (De Petrocellis et al., 2004De Petrocellis L. Cascio M.G. Di Marzo V. The endocannabinoid system: a general view and latest additions.Br. J. Pharmacol. 2004; 141: 765-774Crossref PubMed Scopus (359) Google Scholar, Piomelli, 2003Piomelli D. The molecular logic of endocannabinoid signalling.Nat. Rev. Neurosci. 2003; 4: 873-884Crossref PubMed Scopus (1309) Google Scholar), and more recently described ligands including the peptide endocannabinoids, the so-called pepcans (Bauer et al., 2012Bauer M. Chicca A. Tamborrini M. Eisen D. Lerner R. Lutz B. Poetz O. Pluschke G. Gertsch J. Identification and quantification of a new family of peptide endocannabinoids (Pepcans) showing negative allosteric modulation at CB1 receptors.J. Biol. Chem. 2012; 287: 36944-36967Crossref PubMed Scopus (84) Google Scholar, Hofer et al., 2015Hofer S.C. Ralvenius W.T. Gachet M.S. Fritschy J.M. Zeilhofer H.U. Gertsch J. Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla.Neuropharmacology. 2015; 98: 78-89Crossref PubMed Scopus (0) Google Scholar), the lipid lipoxin A4 (Pamplona et al., 2012Pamplona F.A. Ferreira J. Menezes de Lima Jr., O. Duarte F.S. Bento A.F. Forner S. Villarinho J.G. Bellocchio L. Wotjak C.T. Lerner R. et al.Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor.Proc. Natl. Acad. Sci. USA. 2012; 109: 21134-21139Crossref PubMed Scopus (0) Google Scholar) and the neurosteroid pregnenolone (Vallée et al., 2014Vallée M. Vitiello S. Bellocchio L. Hébert-Chatelain E. Monlezun S. Martin-Garcia E. Kasanetz F. Baillie G.L. Panin F. Cathala A. et al.Pregnenolone can protect the brain from cannabis intoxication.Science. 2014; 343: 94-98Crossref PubMed Scopus (104) Google Scholar). The enzymatic machinery for synthesis and degradation of endocannabinoids is also part of the ECS (De Petrocellis et al., 2004De Petrocellis L. Cascio M.G. Di Marzo V. The endocannabinoid system: a general view and latest additions.Br. J. Pharmacol. 2004; 141: 765-774Crossref PubMed Scopus (359) Google Scholar, Piomelli, 2003Piomelli D. The molecular logic of endocannabinoid signalling.Nat. Rev. Neurosci. 2003; 4: 873-884Crossref PubMed Scopus (1309) Google Scholar). Endocannabinoids have been identified in many species (De Petrocellis et al., 1999De Petrocellis L. Melck D. Bisogno T. Milone A. Di Marzo V. Finding of the endocannabinoid signalling system in Hydra, a very primitive organism: possible role in the feeding response.Neuroscience. 1999; 92: 377-387Crossref PubMed Scopus (0) Google Scholar, McPartland et al., 2006aMcPartland J.M. Agraval J. Gleeson D. Heasman K. Glass M. Cannabinoid receptors in invertebrates.J. Evol. Biol. 2006; 19: 366-373Crossref PubMed Scopus (0) Google Scholar, McPartland et al., 2006bMcPartland J.M. Matias I. Di Marzo V. Glass M. Evolutionary origins of the endocannabinoid system.Gene. 2006; 370: 64-74Crossref PubMed Scopus (0) Google Scholar). However, orthologs of CB1 receptors with various degrees of homology have been identified in fishes, amphibians, birds, and mammals (Elphick, 2012Elphick M.R. The evolution and comparative neurobiology of endocannabinoid signalling.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2012; 367: 3201-3215Crossref PubMed Scopus (0) Google Scholar). Insects do not have cannabinoid receptors (McPartland et al., 2001McPartland J. Di Marzo V. De Petrocellis L. Mercer A. Glass M. Cannabinoid receptors are absent in insects.J. Comp. Neurol. 2001; 436: 423-429Crossref PubMed Scopus (0) Google Scholar), whereas the genome of non-verebrate cordates, such as the sea squirt, contain a gene expressing a combined CB1-CB2 receptor (Elphick, 2012Elphick M.R. The evolution and comparative neurobiology of endocannabinoid signalling.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2012; 367: 3201-3215Crossref PubMed Scopus (0) Google Scholar). CB1 receptor orthologs are likely present in reptiles (St John et al., 2012St John J.A. Braun E.L. Isberg S.R. Miles L.G. Chong A.Y. Gongora J. Dalzell P. Moran C. Bed'hom B. Abzhanov A. et al.Sequencing three crocodilian genomes to illuminate the evolution of archosaurs and amniotes.Genome Biol. 2012; 13: 415Crossref PubMed Scopus (70) Google Scholar). In this section, we will briefly describe general aspects of the molecular organization of the ECS in mammals, particularly in humans and rodents. Several excellent reviews exist on this subject, and we refer the reader to them for a more exhaustive discussion (Lutz et al., 2015Lutz B. Marsicano G. Maldonado R. Hillard C.J. The endocannabinoid system in guarding against fear, anxiety and stress.Nat. Rev. Neurosci. 2015; 16: 705-718Crossref PubMed Scopus (70) Google Scholar, Mechoulam et al., 2014Mechoulam R. Hanuš L.O. Pertwee R. Howlett A.C. Early phytocannabinoid chemistry to endocannabinoids and beyond.Nat. Rev. Neurosci. 2014; 15: 757-764Crossref PubMed Scopus (71) Google Scholar, Piomelli, 2003Piomelli D. The molecular logic of endocannabinoid signalling.Nat. Rev. Neurosci. 2003; 4: 873-884Crossref PubMed Scopus (1309) Google Scholar, Silvestri and Di Marzo, 2013Silvestri C. Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders.Cell Metab. 2013; 17: 475-490Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). Typical endocannabinoids have the peculiarity of being lipids derived from arachidonic acid (Piomelli, 2003Piomelli D. The molecular logic of endocannabinoid signalling.Nat. Rev. Neurosci. 2003; 4: 873-884Crossref PubMed Scopus (1309) Google Scholar). This characteristic explains why these endocannabinoids are not stored but mostly produced on demand by cell membranes. Water-soluble endogenous mediators are generally kept in the intracellular compartment in lipid vesicles that would be unable to hold lipid molecules. Classic lipid endocannabinoids are believed to originate from cellular membranes and to be mobilized upon specific stimuli (Piomelli, 2003Piomelli D. The molecular logic of endocannabinoid signalling.Nat. Rev. Neurosci. 2003; 4: 873-884Crossref PubMed Scopus (1309) Google Scholar). Little is known concerning the storage and release of pepcans; however, they likely use vesicle-dependent mechanisms (Bauer et al., 2012Bauer M. Chicca A. Tamborrini M. Eisen D. Lerner R. Lutz B. Poetz O. Pluschke G. Gertsch J. Identification and quantification of a new family of peptide endocannabinoids (Pepcans) showing negative allosteric modulation at CB1 receptors.J. Biol. Chem. 2012; 287: 36944-36967Crossref PubMed Scopus (84) Google Scholar, Hofer et al., 2015Hofer S.C. Ralvenius W.T. Gachet M.S. Fritschy J.M. Zeilhofer H.U. Gertsch J. Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla.Neuropharmacology. 2015; 98: 78-89Crossref PubMed Scopus (0) Google Scholar). The mechanisms of production, storage, and release of the allosteric CB1 receptor enhancer lipoxin A4 in the brain are not known, but they might be similar to the ones described in blood cells, through transcellular generation (McMahon et al., 2001McMahon B. Mitchell S. Brady H.R. Godson C. Lipoxins: revelations on resolution.Trends Pharmacol. Sci. 2001; 22: 391-395Abstract F
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