Role of metabotropic glutamate receptors in the regulation of pancreatic functions

Abstract

The pancreas consists of two major divisions, the exocrine and the endocrine pancreas. Recent data from our laboratory have shown that the functions of the two divisions are under modulatory regulation by separate neurocircuits that originate in the dorsal motor nucleus of the vagus (DMV). Metabotropic glutamate receptors (mGluRs) are expressed throughout the central nervous system and have been implicated in the modulation of synaptic transmission. mGluRs consist of three groups of receptors, which can be distinguished based on their pharmacological properties and second messenger systems. Group I mGluRs predominantly increase, whereas group II and III mGluRs decrease synaptic transmission. Group II and group III mGluRs are present on excitatory and inhibitory synaptic terminals impinging on pancreas-projecting DMV neurons. We have shown that group II mGluRs regulate both exocrine pancreatic secretions and insulin release, whereas group III mGluRs only regulate insulin release. Several mGluR agonists and antagonists have been shown to have clinical uses for disorders accompanied by abnormal synaptic transmission, including anxiety and Parkinson’s disease. Moreover, a negative allosteric modulator of Group I mGluRs is effective in alleviating symptoms of gastroesophageal reflux disease (GERD). Since the role of the three mGluR groups in mediating different gastrointestinal (GI) functions appears to be highly specific, the use of agonists or antagonists directed at a single receptor group could potentially provide highly selective targets for the treatment of GI disorders including GERD, functional dyspepsia and acute pancreatitis.

Vagal neurocircuitry and its influence on gastric motility

“…In addition, these vagal afferent fibres probably also project onto the dendrites of DMV neurons that extend into the NTS gelatinosus 64 , although the neurotransmitter used has not yet been identified. Concomitant to the activation of ionotropic receptors, glutamate released from vagal afferent fibres also activates metabotropic glutamate receptors (mGluRs), which produce long-lasting effects on the excitability of vagal afferent fibres and synaptic transmission to NTS and DMV neurons 7,65–70 . Of particu lar importance for the vagally mediated modu lation of gastric motility is the ongoing activation of group II and III mGluRs, which inhibit adenylate cyclase and consequently inhibit GABAergic synaptic transmission selectively 71,72 .…”

Neural Control of the Pancreas

“…In fact, microinjections of ionotropic glutamate receptor antagonist kynurenic acid into the DMV do not affect pancreatic exocrine secretion in control rats (9). However, glutamatergic synapses impinging on pancreas-projecting DMV neurons are subject to modulation by various neurotransmitters and hormones (10). Similar to GABAergic synapses, glutamatergic synapses are modulated by PP, GLP-1 and CCK, as well as by metabotropic glutamate receptors (8,16,(77)(78)(79).…”

“…Although NTS neurons express a wide variety of neurotransmitters and neuromodulators, NTS projects to the DMV primarily via glutamatergic, GABAergic and catecholaminergic inputs (73). Despite this relatively simple neurochemistry, NTS-DMV synapses display a great deal of plasticity and can be modulated by numerous neurotransmitters, neuromodulators, hormones and physiological conditions (10).…”

“…In addition to modulating pancreatic functions directly, GABAergic synapses in the DMV are subject to modulation by various other neurotransmitters and hormones. Studies from our laboratory have shown that GABAergic synapses impinging on pancreas-projecting DMV neurons can be modulated by PP, GLP-1, CCK, as well as metabotropic glutamate receptor agonists (10).…”

“…Unlike the ionotropic glutamate receptors, which couple to ion channels and mediate fast synaptic transmission, mGluRs are members of G-protein coupled receptor (GPCR) family of receptors and couple to different second messenger systems. There are eight known subtypes of mGluRs, which belong to three different groups (group I II and III mGluRs), each of which has unique pharmacological characteristics (10).…”