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Enteric purinergic signaling: Shaping the “brain in the gut”
Neuropharmacology 95 (2015) 477e478
Contents lists available at ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Commentary
Enteric purinergic signaling: Shaping the “brain in the gut” Luca Antonioli a, Corrado Blandizzi a, *, Maria Cecilia Giron b a b
Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
a r t i c l e i n f o Article history: Received 27 March 2015 Accepted 9 April 2015 Available online 14 May 2015
The enteric nervous system (ENS), commonly designated as the “brain in the gut”, regulates intestinal homeostasis through a number of different cell types with the goal of integrating mechanical and chemical stimuli, interneuronal communication and efferent outputs, to ensure a fine coordination of motor patterns, secretions and absorption of digested nutrients (Schemann, 2005). The ENS comprises a neural network arranged in two major ganglionated structures, designated as myenteric plexus (Auerbach's, located between the longitudinal and circular muscle layers of the muscularis externa) and submucosal plexus (Meissner's, located beneath the mucosa) (Grundy and Schemann, 2007; Wood, 2008). Overall, there is a general division of functional tasks assigned to neurons located in the two plexuses, such that submucosal neurons predominantly innervate the mucosa and regulate enteric secretion, absorption, and blood flow, whereas myenteric neurons are primarily involved in the control of motor functions (Grundy and Schemann, 2007; Wood, 2008). Of note, the ENS participates also in the regulation of gut immune/inflammatory processes (De Jonge, 2013). In the digestive tract, tight interactions between the neuronal elements of ENS and the enteric immune cells, involved in patrolling the gut lumen, ensure effective motor and secretory adaptive changes, aimed at stemming pathogenic assaults as well as to normalize abnormal intestinal activities (De Jonge, 2013). In particular, these neuroimmune interactions progress through sequential steps, which begin with the immune detection of luminal threat signals
DOI of original article: http://dx.doi.org/10.1016/j.neuropharm.2015.02.014. * Corresponding author. Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy. Tel.: þ39 050 2218754; fax: þ39 050 2218758. E-mail address: [email protected] (C. Blandizzi). http://dx.doi.org/10.1016/j.neuropharm.2015.04.021 0028-3908/© 2015 Elsevier Ltd. All rights reserved.
and proceed with transferring messages back and forth between the ENS and the surrounding intestinal tissue entities, in order to ensure a neural interpretation of the stimuli, and the selection of the most suitable neural program, resulting in coordinated mucosal secretion and propulsive motor events, that lead to a quick clearance of the threat from gut lumen (Wood, 2004). This extreme ductility of action, which is a hallmark of the ENS, is supported by a broad range of reparative, maintenance and adaptive properties, aimed at triggering specific responses on the basis of the different physiological (i.e, development and aging) or detrimental conditions (i.e. infections, hypoxia and inflammation) (Brierley and Linden, 2014). These properties, included in the concept of enteric neuroplasticity, comprise a wide range of structural, functional or chemical phenotypic modifications evolved to maintain the digestive homeostasis as well as to trigger adaptive responses and/or reparative events aimed at normalizing altered gut functions and relieving associated symptoms (Brierley and Linden, 2014). The complex network between immune/inflammatory cells and ENS can be finely tuned by several mediators, and increasing evidence highlights a prominent and critical role of purinergic pathways in shaping the activity of the “brain in the gut” (Burnstock, 2008; Christofi, 2008; Antonioli et al., 2008). The first appreciation of the relevance of purines in the physiological control of digestive functions can be dated back to early 1970s, when pioneering studies by Burnstock showed that adenosine triphosphate (ATP) and related nucleotides/nucleosides (adenosine diphosphate ADP, adenosine monophosphate AMP and adenosine), previously considered merely as ubiquitous biochemical sources of energy, functioned as transmitters at intestinal level, with significant contributions to the physiology of enteric neuromuscular activity (Burnstock, 2009). These initial observations fostered a strong
478
L. Antonioli et al. / Neuropharmacology 95 (2015) 477e478
interest on the purinergic system, spurring scientific attention towards a critical evaluation of purine involvement in the regulation of gastrointestinal functions (Christofi, 2008; Antonioli et al., 2008). The wide and heterogeneous expression of purinergic receptors throughout the gut as well as the wide distribution of synthetic/ catabolic enzymes and transporters in the neuromuscular compartment of the digestive tract in both humans and rodents (Christofi et al., 2001; Antonioli et al., 2008), together with functional experiments on animal models, have corroborated the evidence of a pivotal involvement of purines in the physiological regulation of gut reflexes (Christofi, 2001; Burnstock, 2008; Antonioli et al., 2008, 2013; Christofi, 2008). Despite the above concepts are supported by a body of data from preclinical models, little information is available about the role of purinergic signaling in the modulation of human ENS. In addition, the translation of current knowledge on purinergic signaling from preclinical models to human ENS is complicated by differences in the neurochemistry, neurophysiology, and receptor pharmacology of enteric neurons among species. In this context, the data provided by Christofi and coworkers, in the present issue ~ of Neuropharmacology (Lin an-Rico et al., 2015) add further detail and nuance to our understanding of the complex role played by purinergic pathways in the regulation of human submucosal plexus, thus corroborating further the evidence that supports a major role for purine nucleotides as neurotransmitters in the human ENS. In particular, the authors present solid evidence on the dual activity exerted by purines in the human submucous plexus, with an excitatory action exerted by ATP and driven by P2X1, P2X2 and P2X3 receptors, and an inhibitory control mediated ~a n-Rico et al., 2015). These by P2Y and A3 adenosine receptors (Lin findings support the hypothesis that a differential recruitment of purine receptor subtypes can be operated by the segregation of purine bioavailability in discrete microenvironments within the submucosal plexus through a membrane network of appropriate receptors, enzymes and nucleoside transporters, rather than by each distinct factor (Suzuki et al., 2013). Such hypothesis is consistent with the concept of “enteric purinome” (Antonioli et al., 2011), which comprises a dynamic membrane network of appropriate receptors, enzymes and nucleoside transporters, aimed at finely modulating the magnitude and duration of purinergic responses as well as driving the shift from ATPergic to adenosinergic responses in specific districts under different conditions (Antonioli et al., 2013). For these reasons, a holistic view of purinergic signaling in the human submucosal plexus appears of extreme interest to better contextualize the fascinating evidences reported ~ by Lin an-Rico et al. (2015), and define more tightly the physiological role of purines in finely tuning neurotransmission in the human ENS. Another point deserving consideration, to get an exhaustive picture of the enteric purinergic system, is the possible existence of an interplay between purinergic receptors. It is, indeed, well known that purinergic receptors can give rise to heterodimers, which, operating specific changes in signal transduction, as compared with individual receptors, represent a further way that can be employed by the system for the fine tuning of purinergic signalling (Suzuki et al., 2013). In this regard, the presence of a co-localization of
P2X1/P2X2 and P2X2/P2X3 receptors, as described by Christofi and ~a n-Rico et al., 2015), allows to hypothesize the colleagues (Lin occurrence of functional crosstalks among them. However, the actual occurrence of a heterodimerization of purine receptors in the human submucosal plexus has not been specifically evaluated and deserves further experimental investigations. Overall, the findings reported by Christofi and coworkers, taken together with current knowledge, spur the performance of future evaluations aimed at characterizing how, and to what extent, the enteric purinome is involved in the regulation of intestinal homeostasis in humans, as well as its role in the pathophysiology of bowel disorders. A better understanding of the neuropharmacology of purinergic pathways is indeed highly needed, given the role of “ideal bridge” played by this system between the enteric neuromuscular compartment and the immune system. Expanding our knowledge in this field would allow to gain more insights into the pathophysiological mechanisms underlying several intestinal disorders (i.e. inflammatory bowel diseases, irritable bowel syndrome and diarrheal disorders), characterized by alterations of immuneneuronal interplays, and ultimately to pave the way towards innovative therapeutic approaches for the management of such disorders. References Antonioli, L., Fornai, M., Colucci, R., Ghisu, N., Tuccori, M., Del Tacca, M., Blandizzi, C., 2008. Regulation of enteric functions by adenosine: pathophysiological and pharmacological implications. Pharmacol. Ther. 120, 233e253. Antonioli, L., Fornai, M., Colucci, R., Tuccori, M., Blandizzi, C., 2011. A holistic view of adenosine in the control of intestinal neuromuscular functions: the enteric ‘purinome’ concept. Br. J. Pharmacol. 164, 1577e1579. Antonioli, L., Colucci, R., Pellegrini, C., Giustarini, G., Tuccori, M., Blandizzi, C., Fornai, M., 2013. The role of purinergic pathways in the pathophysiology of gut diseases: pharmacological modulation and potential therapeutic applications. Pharmacol. Ther. 139, 157e188. Brierley, S.M., Linden, D.R., 2014. Neuroplasticity and dysfunction after gastrointestinal inflammation. Nat. Rev. Gastroenterol. Hepatol. 11, 611e627. Burnstock, G., 2008. Purinergic receptors as future targets for treatment of functional GI disorders. Gut 57, 1193e1194. Burnstock, G., 2009. Purinergic cotransmission. Exp. Physiol. 94, 20e24. Christofi, F.L., Zhang, H., Yu, J.G., Guzman, J., Xue, J., Kim, M., Wang, Y.Z., Cooke, H.J., 2001. Differential gene expression of adenosine A1, A2a, A2b, and A3 receptors in the human enteric nervous system. J. Comp. Neurol. 439, 46e64. Christofi, F.L., 2001. Unlocking mysteries of gut sensory transmission: is adenosine the key? News Physiol. Sci. 16, 201e207. Christofi, F.L., 2008. Purinergic receptors and gastrointestinal secretomotor function. Purinergic Signal. 4, 213e236. De Jonge, W.J., 2013. The gut's little brain in control of intestinal immunity. ISRN Gastroenterol. 2013, 630159. Grundy, D., Schemann, M., 2007. Enteric nervous system. Curr. Opin. Gastroenterol. 23, 121e126. ~ Lin an-Rico, A., Wunderlich, J.E., Enneking, J.T., Tso, D.R., Grants, I., Williams, K.C., Otey, A., Michel, K., Schemann, M., Needleman, B., Harzman, A., Christofi, F.L., 2015. Neuropharmacology of purinergic receptors in human submucous plexus: involvement of P2X(1), P2X(2), P2X(3) channels, P2Y and A(3) metabotropic receptors in neurotransmission. Neuropharmacology 95, 83e99. Schemann, M., 2005. Control of gastrointestinal motility by the “gut brain”dthe enteric nervous system. J. Pediatr. Gastroenterol. Nutr. 41 (Suppl. 1), S4eS6. Suzuki, T., Namba, K., Mizuno, N., Nakata, H., 2013. Hetero-oligomerization and specificity changes of G protein-coupled purinergic receptors: novel insight into diversification of signal transduction. Methods Enzymol. 521, 239e257. Wood, J.D., 2004. Enteric neuroimmunophysiology and pathophysiology. Gastroenterology 127, 635e657. Wood, J.D., 2008. Enteric nervous system: reflexes, pattern generators and motility. Curr. Opin. Gastroenterol. 24, 149e158.
Contents lists available at ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Commentary
Enteric purinergic signaling: Shaping the “brain in the gut” Luca Antonioli a, Corrado Blandizzi a, *, Maria Cecilia Giron b a b
Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
a r t i c l e i n f o Article history: Received 27 March 2015 Accepted 9 April 2015 Available online 14 May 2015
The enteric nervous system (ENS), commonly designated as the “brain in the gut”, regulates intestinal homeostasis through a number of different cell types with the goal of integrating mechanical and chemical stimuli, interneuronal communication and efferent outputs, to ensure a fine coordination of motor patterns, secretions and absorption of digested nutrients (Schemann, 2005). The ENS comprises a neural network arranged in two major ganglionated structures, designated as myenteric plexus (Auerbach's, located between the longitudinal and circular muscle layers of the muscularis externa) and submucosal plexus (Meissner's, located beneath the mucosa) (Grundy and Schemann, 2007; Wood, 2008). Overall, there is a general division of functional tasks assigned to neurons located in the two plexuses, such that submucosal neurons predominantly innervate the mucosa and regulate enteric secretion, absorption, and blood flow, whereas myenteric neurons are primarily involved in the control of motor functions (Grundy and Schemann, 2007; Wood, 2008). Of note, the ENS participates also in the regulation of gut immune/inflammatory processes (De Jonge, 2013). In the digestive tract, tight interactions between the neuronal elements of ENS and the enteric immune cells, involved in patrolling the gut lumen, ensure effective motor and secretory adaptive changes, aimed at stemming pathogenic assaults as well as to normalize abnormal intestinal activities (De Jonge, 2013). In particular, these neuroimmune interactions progress through sequential steps, which begin with the immune detection of luminal threat signals
DOI of original article: http://dx.doi.org/10.1016/j.neuropharm.2015.02.014. * Corresponding author. Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy. Tel.: þ39 050 2218754; fax: þ39 050 2218758. E-mail address: [email protected] (C. Blandizzi). http://dx.doi.org/10.1016/j.neuropharm.2015.04.021 0028-3908/© 2015 Elsevier Ltd. All rights reserved.
and proceed with transferring messages back and forth between the ENS and the surrounding intestinal tissue entities, in order to ensure a neural interpretation of the stimuli, and the selection of the most suitable neural program, resulting in coordinated mucosal secretion and propulsive motor events, that lead to a quick clearance of the threat from gut lumen (Wood, 2004). This extreme ductility of action, which is a hallmark of the ENS, is supported by a broad range of reparative, maintenance and adaptive properties, aimed at triggering specific responses on the basis of the different physiological (i.e, development and aging) or detrimental conditions (i.e. infections, hypoxia and inflammation) (Brierley and Linden, 2014). These properties, included in the concept of enteric neuroplasticity, comprise a wide range of structural, functional or chemical phenotypic modifications evolved to maintain the digestive homeostasis as well as to trigger adaptive responses and/or reparative events aimed at normalizing altered gut functions and relieving associated symptoms (Brierley and Linden, 2014). The complex network between immune/inflammatory cells and ENS can be finely tuned by several mediators, and increasing evidence highlights a prominent and critical role of purinergic pathways in shaping the activity of the “brain in the gut” (Burnstock, 2008; Christofi, 2008; Antonioli et al., 2008). The first appreciation of the relevance of purines in the physiological control of digestive functions can be dated back to early 1970s, when pioneering studies by Burnstock showed that adenosine triphosphate (ATP) and related nucleotides/nucleosides (adenosine diphosphate ADP, adenosine monophosphate AMP and adenosine), previously considered merely as ubiquitous biochemical sources of energy, functioned as transmitters at intestinal level, with significant contributions to the physiology of enteric neuromuscular activity (Burnstock, 2009). These initial observations fostered a strong
478
L. Antonioli et al. / Neuropharmacology 95 (2015) 477e478
interest on the purinergic system, spurring scientific attention towards a critical evaluation of purine involvement in the regulation of gastrointestinal functions (Christofi, 2008; Antonioli et al., 2008). The wide and heterogeneous expression of purinergic receptors throughout the gut as well as the wide distribution of synthetic/ catabolic enzymes and transporters in the neuromuscular compartment of the digestive tract in both humans and rodents (Christofi et al., 2001; Antonioli et al., 2008), together with functional experiments on animal models, have corroborated the evidence of a pivotal involvement of purines in the physiological regulation of gut reflexes (Christofi, 2001; Burnstock, 2008; Antonioli et al., 2008, 2013; Christofi, 2008). Despite the above concepts are supported by a body of data from preclinical models, little information is available about the role of purinergic signaling in the modulation of human ENS. In addition, the translation of current knowledge on purinergic signaling from preclinical models to human ENS is complicated by differences in the neurochemistry, neurophysiology, and receptor pharmacology of enteric neurons among species. In this context, the data provided by Christofi and coworkers, in the present issue ~ of Neuropharmacology (Lin an-Rico et al., 2015) add further detail and nuance to our understanding of the complex role played by purinergic pathways in the regulation of human submucosal plexus, thus corroborating further the evidence that supports a major role for purine nucleotides as neurotransmitters in the human ENS. In particular, the authors present solid evidence on the dual activity exerted by purines in the human submucous plexus, with an excitatory action exerted by ATP and driven by P2X1, P2X2 and P2X3 receptors, and an inhibitory control mediated ~a n-Rico et al., 2015). These by P2Y and A3 adenosine receptors (Lin findings support the hypothesis that a differential recruitment of purine receptor subtypes can be operated by the segregation of purine bioavailability in discrete microenvironments within the submucosal plexus through a membrane network of appropriate receptors, enzymes and nucleoside transporters, rather than by each distinct factor (Suzuki et al., 2013). Such hypothesis is consistent with the concept of “enteric purinome” (Antonioli et al., 2011), which comprises a dynamic membrane network of appropriate receptors, enzymes and nucleoside transporters, aimed at finely modulating the magnitude and duration of purinergic responses as well as driving the shift from ATPergic to adenosinergic responses in specific districts under different conditions (Antonioli et al., 2013). For these reasons, a holistic view of purinergic signaling in the human submucosal plexus appears of extreme interest to better contextualize the fascinating evidences reported ~ by Lin an-Rico et al. (2015), and define more tightly the physiological role of purines in finely tuning neurotransmission in the human ENS. Another point deserving consideration, to get an exhaustive picture of the enteric purinergic system, is the possible existence of an interplay between purinergic receptors. It is, indeed, well known that purinergic receptors can give rise to heterodimers, which, operating specific changes in signal transduction, as compared with individual receptors, represent a further way that can be employed by the system for the fine tuning of purinergic signalling (Suzuki et al., 2013). In this regard, the presence of a co-localization of
P2X1/P2X2 and P2X2/P2X3 receptors, as described by Christofi and ~a n-Rico et al., 2015), allows to hypothesize the colleagues (Lin occurrence of functional crosstalks among them. However, the actual occurrence of a heterodimerization of purine receptors in the human submucosal plexus has not been specifically evaluated and deserves further experimental investigations. Overall, the findings reported by Christofi and coworkers, taken together with current knowledge, spur the performance of future evaluations aimed at characterizing how, and to what extent, the enteric purinome is involved in the regulation of intestinal homeostasis in humans, as well as its role in the pathophysiology of bowel disorders. A better understanding of the neuropharmacology of purinergic pathways is indeed highly needed, given the role of “ideal bridge” played by this system between the enteric neuromuscular compartment and the immune system. Expanding our knowledge in this field would allow to gain more insights into the pathophysiological mechanisms underlying several intestinal disorders (i.e. inflammatory bowel diseases, irritable bowel syndrome and diarrheal disorders), characterized by alterations of immuneneuronal interplays, and ultimately to pave the way towards innovative therapeutic approaches for the management of such disorders. References Antonioli, L., Fornai, M., Colucci, R., Ghisu, N., Tuccori, M., Del Tacca, M., Blandizzi, C., 2008. Regulation of enteric functions by adenosine: pathophysiological and pharmacological implications. Pharmacol. Ther. 120, 233e253. Antonioli, L., Fornai, M., Colucci, R., Tuccori, M., Blandizzi, C., 2011. A holistic view of adenosine in the control of intestinal neuromuscular functions: the enteric ‘purinome’ concept. Br. J. Pharmacol. 164, 1577e1579. Antonioli, L., Colucci, R., Pellegrini, C., Giustarini, G., Tuccori, M., Blandizzi, C., Fornai, M., 2013. The role of purinergic pathways in the pathophysiology of gut diseases: pharmacological modulation and potential therapeutic applications. Pharmacol. Ther. 139, 157e188. Brierley, S.M., Linden, D.R., 2014. Neuroplasticity and dysfunction after gastrointestinal inflammation. Nat. Rev. Gastroenterol. Hepatol. 11, 611e627. Burnstock, G., 2008. Purinergic receptors as future targets for treatment of functional GI disorders. Gut 57, 1193e1194. Burnstock, G., 2009. Purinergic cotransmission. Exp. Physiol. 94, 20e24. Christofi, F.L., Zhang, H., Yu, J.G., Guzman, J., Xue, J., Kim, M., Wang, Y.Z., Cooke, H.J., 2001. Differential gene expression of adenosine A1, A2a, A2b, and A3 receptors in the human enteric nervous system. J. Comp. Neurol. 439, 46e64. Christofi, F.L., 2001. Unlocking mysteries of gut sensory transmission: is adenosine the key? News Physiol. Sci. 16, 201e207. Christofi, F.L., 2008. Purinergic receptors and gastrointestinal secretomotor function. Purinergic Signal. 4, 213e236. De Jonge, W.J., 2013. The gut's little brain in control of intestinal immunity. ISRN Gastroenterol. 2013, 630159. Grundy, D., Schemann, M., 2007. Enteric nervous system. Curr. Opin. Gastroenterol. 23, 121e126. ~ Lin an-Rico, A., Wunderlich, J.E., Enneking, J.T., Tso, D.R., Grants, I., Williams, K.C., Otey, A., Michel, K., Schemann, M., Needleman, B., Harzman, A., Christofi, F.L., 2015. Neuropharmacology of purinergic receptors in human submucous plexus: involvement of P2X(1), P2X(2), P2X(3) channels, P2Y and A(3) metabotropic receptors in neurotransmission. Neuropharmacology 95, 83e99. Schemann, M., 2005. Control of gastrointestinal motility by the “gut brain”dthe enteric nervous system. J. Pediatr. Gastroenterol. Nutr. 41 (Suppl. 1), S4eS6. Suzuki, T., Namba, K., Mizuno, N., Nakata, H., 2013. Hetero-oligomerization and specificity changes of G protein-coupled purinergic receptors: novel insight into diversification of signal transduction. Methods Enzymol. 521, 239e257. Wood, J.D., 2004. Enteric neuroimmunophysiology and pathophysiology. Gastroenterology 127, 635e657. Wood, J.D., 2008. Enteric nervous system: reflexes, pattern generators and motility. Curr. Opin. Gastroenterol. 24, 149e158.