Journal of Pre-Clinical and Clinical Research, Vol 1, No 2, 107-111 REVIEW www.jpccr.eu Role of peripheral glutamate receptors in regulation of gastric secretion and motor function of stomach Tetyana Falalyeyeva, Tetyana Beregova Pharmaco-Physiology Department, Taras Shevchenko State University, Kiev, Ukraine Abstract: Anatomical, physiological and pharmacological evidence suggests that glutamate is neurotransmitter in the peripheral nervous system. The aim of this review is to show the distribution of the glutamatergic system within the mammalian gastric wall and how this system regulates gastric functions. There have been reports that different types of glutamate receptors are involved in regulation of gastric acid secretion, gastric motility and food intake. Key words: glutamate receptors, glutamatergic neurons, stomach, gastric acid secretion, gastric motility, food intake INTRODUCTION GLUTAMATERGIC NEURONS IN THE STOMACH The enteric nervous system (ENS) is the only region of Anatomical, physiological and pharmacological evidence the peripheral nervous system that is intrinsically capable of suggests that L-Glu is an excitatory neurotransmitter in the mediating reflex activity [1, 2]. This activity is made possible by peripheral nervous system [2, 9]. The glutamate receptors in the presence within the gastrointestinal tract of microcircuits rat gastrointestinal tract are located on cholinergic nerves that contain the necessary primary afferent neurons and prejunctionally to enhance nerve-mediated responses. interneurons, as well as the excitatory and inhibitory motor Glutamate immunoreactivities have been detected in neurons that innervate gastrointestinal smooth muscle and cholinergic enteric neurons. The immunoreactivities of both glands. The complexity of the functions controlled by the NMDA and non-NMDA receptors are also detected in neurons ENS is reflected in an equally complex organization that in submucosal and myenteric plexuses [2]. resembles that of the central nervous system (CNS) more Immunohistochemical studies support the notion that than the remainder of the peripheral nervous system. Many glutamatergic neurons are present in the stomach [9]. The different classes of neurotransmitters have been found in the distribution of glutamatergic neurons and their processes in ENS, including most of those known also to be present in the both myenteric ganglia and circular muscle are heterogeneous CNS. Glutamate, the major excitatory neurotransmitter of within the stomach [10]. Different experimental models clearly the brain [3, 4], seems to be a conspicuous exception in that it suggest that most of the glutamate-containing axons in the has not previously been found to be a neurotransmitter in the intestinal and stomach walls originate from cell bodies within ENS. As is the case in other parts of the brain, glutamatergic the myenteric and submucous plexus [11, 12]. Furthermore, circuits in the stomach are generally confined to networks of there is evidence suggesting that the gastrointestinal tract interneurons in the ENS. Through various feedback and feed- is also innervated by extrinsic glutamate-immunoreactive forward loops, glutamatergic interneurons react to certain axons. Axon terminals contain large numbers of small and aspects of the gastric function. Enteric glutamatergic fibres clear synaptic vesicles [13-18]. Glutamatergic varicosities, are profuse, ramifying throughout the ganglionated and non- which often contain choline acetyltransferase (ChAT) and the ganglionated enteric nerve networks of the gastrointestinal vesicular acetylcholine transporter, are apposed to a subset of wall [2]. The glutamatergic neurons have been shown to be neuronal cell bodies in the submucous and myenteric plexus present in the submucous and myenteric plexuses [5-8]. There in the stomach [18]. The submucosal neurons that contain is evidence indicating a role of glutamatergic neurons in the ChAT are thought to be the primary afferent neurons that regulation of gastric motility, secretion and gastric reflexes project to the mucosa and respond to the sensory stimuli [9]. However, the receptor subtypes and mechanism that from the gastrointestinal tract [19]. Thus, some of the enteric mediate the effects of L-Glutamate (L-Glu) in the stomach glutamatergic neurons are likely to be sensory neurons and are still poorly understood. The aim of this review is to glutamate may be involved in the transfer of sensory information show the distribution of the glutamatergic system within from the mucosa to the enteric plexuses. The synapse in the the mammalian gastric wall and describe the regulation of ENS appears to possess a high-affinity glutamate uptake gastric functions by this system. system [20]. In in situ hybridization studies, mRNA coding for the glutamate NMDA receptor has been expressed in rat enteric neurons in the stomach. Enteric neurons expressing mRNA for both NMDA receptors and vasoactive intestinal Corresponding author: Prof. Tetyana Beregova, Pharmaco-Physiology Department, Taras Shevchenko State University, Akad. Glushkov av. 2, Kiev, Ukraine. polypeptide (VIP) are found in the myenteric and submucosal E-mail: [email protected] ganglia. Received: 12 December 2007; accepted: 21 December 2007 108 The Role of peripheral glutamate receptors in gastric secretion Tetyana Falalyeyeva et al TYPES OF GLUTAMATE RECEPTORS IN STOMACH as does CNS [38], which are members of the G-protein-coupled receptor family. At present, eight different mGluRs have been There are two main classes of receptors for glutamate, cloned, termed from mGluR1 to mGluR8 [39]. Based on their namely, ionotropic glutamate receptors (ligand-gated ion sequence similarities, pharmacology and signal transduction channels) and metabotropic glutamate receptors (coupled mechanism, mGluRs are classified into three groups. to G proteins) [20, 21]. Ionotropic glutamate receptors Group I receptors (mGluR1 and mGluR5), which are – which can be further divided into N-methyl-D-aspartate coupled to phospholipase C, exert their effects by activating (NMDA) and non-NMDA receptors – are responsible for protein kinase C and releasing Ca2+ from intracellular stores. synaptic transmission and plasticity [22-24]. Both ionotropic Group II (mGluR2 and mGluR3) and group III (mGluR4 and metabotropic glutamate receptors have been shown to and mGluR6-mGluR8) receptors are negatively coupled localize in enteric ganglia using immunocytochemistry and to adenylyl cyclase. Group I receptors generally increase in situ hybridization [25-27]. cell excitability by inhibiting K+ channels and are mostly postsynaptic, although presynaptic effects have also been Ionotropic glutamate receptors. Ionotropic glutamate reported. Group II and III receptors are mostly present in (iGlu) receptors are ligand-gated ion channels comprising glutamatergic presynaptic terminals and are believed to three subtypes: NMDA, alpha-amino-3-hydroxy-5-methyl-4- exert their action by inhibiting neurotransmitter release. isoxazole propionate (AMPA), and kainate (KA) receptors. However, the function of metabotropic glutamate receptors NMDA receptors are heteromeric pentamers. The subunits in the stomach is still poorly understood. The subcellular are the products of two gene families, one NRl gene and localization of mGluR receptors in enteric neurons might four NR2 (NR2A–D) genes. Although NRl provides a have functional implications in physiology and pathology of functional receptor, it is thought that NR2 increases the the gastrointestinal tract [9]. activity of the channel. Results from in situ hybridization studies have demonstrated the presence of mRNA for NRl and NMDA [13, 14, 28] in both myenteric and submucosal ROLE OF GLUTAMATE RECEPTORS IN STOMACH ganglia. The distribution pattern of NR1, NR2A and NR2B- containing NMDA receptors in rat stomach is determined 1. Gastric smooth muscle contraction. Peripheral immunohistochemically using specific antibodies against contractile effects of glutamate were demonstrated for the first NR1, NR2A and NR2B [29]. These findings are also consistent time 21 years ago on isolated guinea pig ileum [40]. From that with the idea that the enteric glutamate receptors are involved time, the majority of literature was devoted to investigating in neurogenic motility [18, 30] or secretion of the stomach the effect of different types of glutamate receptors on intestine. [10, 29]. Recently, the NRl subunits have been localized However, several later attempts [41, 42] only partially shed the immunohistochemically in peripheral terminals of primary light on the mechanism of that action. Later, it was established afferent nerves of dorsal root ganglia [29, 31]. In addition, the that there is a difference in functional roles of different types peripheral NMDA receptors are also found in both vagal and of glutamate receptors between the isolated rat fundus and spinal primary afferent in the stomach, where the function of intestine. L-Glu shows a powerful stimulating effect on most NMDA receptors is believed to be involved in gastric motility smooth muscle layers in the stomach. NMDA and kainic acid and gastric secretion [29]. stimulate contraction of isolated rat gastric fundus with almost AMPA receptors are mainly involved in mediating fast identical strength of action, whereas the metabotropic receptor glutamatergic neurotransmission. There are four subunits, agonist ACPD has no effect [43]. The gastric excitatory motor known as GluRl to GluR4 (also called GluRA to GluRD) response is elicited