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 gastro-esophageal 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.

Keywords: Electrophysiology.; Glutamate receptors; Pancreas; Vagus.

Fig. 1

A schematic summary showing the organization of group II and group III mGluRs on synaptic terminals impinging on preganlionic pancreas-projecting DMV neurons. A Distribution of mGluRs on synaptic terminals impinging on DMV neurons that regulate PES. Note that these synaptic terminals express only group II mGluRs. B Distribution of mGluRs on synaptic terminals impinging on DMV neurons that regulate endocrine functions. Group II mGluRs are present on the majority of excitatory and inhibitory synaptic terminals impinging on pancreas-projecting neurons and activation of these receptors increases PES and decreases insulin release. The distribution of group III mGluRs is more limited and their activation decreases insulin release, but has no effect on PES. CCK, cholecystokinin; DMV, dorsal motor nucleus of the vagus; GLP-1 glucagon-like peptide-1; Glu, glutamate; mGluR, metabotropic glutamate receptors; PP pancreatic polypeptide.