Somatostatin receptor on the afferent nerve terminals in the rat hepatoportal area

doi:10.1016/0304-3940(94)11111-U

Neuroscience Letters

Volume 183, Issues 1–2, 2 January 1995, Pages 46-49

https://doi.org/10.1016/0304-3940(94)11111-U Get rights and content

Abstract

To determine whether somatostatin receptor (SSR) actually exists on the nerve terminals in the rat hepatoportal area, the area was immunostained by the labeled streptoavidin-biotin complex method using a monoclonal antibody against rat brain SSR. The SSR staining revealed many fiber arborizations with terminal nodular swellings like the afferent nerve endings in the neural body, which was located beneath the endothelium of the large branches of the intrahepatic portal vein. The results indicate that SSR is expressed on the characteristic structure, adding further evidence for our previous observation which showed the hepatic vagal reception for intraportal somatostatin and the somatostatin-binding neural body as a relevant structure.

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Citation Excerpt :
Following the incretin concept, the enzyme dipeptidylpeptidase (DPP-4), which prototypically inactivates the incretins, was discovered [35,36]. Cleavage of the N-terminus of GLP-1 by DPP-4 converts the active GLP-1-[7–37] and [7–36] – amide to the inactive GLP-1-[9–37] and [9–36] – amide, respectively. Therefore, other strategies based on the inhibition of the DPP4 are now widely used for the treatment of type 2 diabetes.
Glucose homeostasis corresponds to the overall physiological, cellular, and molecular mechanisms which tightly maintain the glycaemia between ∼4.5 and ∼6 mM. The resulting blood glucose concentration is the consequence of a balance between the mechanisms that ensure the entry and the output of glucose in the blood. A dynamic balance needs hence to be perfectly achieved in order to maintain a physiological glycaemic concentration. Specialized cells from the intestine continuously detect changes in glucose concentration and send signals to peripheral tissues and the brain through the vagus nerve. The molecular mechanisms involved in glucose detection have not been perfectly defined but could resemble those from the insulin-secreting beta cells. The brain then integrates the enteric and circulating endocrine signals to generate a new signal towards peripheral tissues such as the pancreas, liver, muscles, and blood vessels. This metabolic reflex is called anticipatory since it allows the peripheral tissues to prepare for the adequate handling of nutrients. Diabetes is associated with an impaired anticipatory reflex, which hampers the proper detection of nutrients and leads to hyperglycaemic episodes. Recently, GLP-1-based therapies have demonstrated the improvement of glucose detection and their efficacy on glycaemic control. Although not yet fully demonstrated, GLP-1-based therapies regulate glucose sensors, which leads to the glycaemic improvement. Certainly other molecular targets could be identified to further generate new therapeutic strategies.
L’homéostasie glucidique correspond à l’ensemble des mécanismes physiologiques, cellulaires, et moléculaires qui ajustent étroitement la glycémie entre 4,5 et 6 mM. Les variations de la glycémie qui résultent de l’entrée ou de la sortie du glucose de l’organisme et du sang doivent sans cesse être corrigées. Un équilibre dynamique est donc mis en place entre les mécanismes responsables de l’utilisation du glucose par les tissus et ceux qui concourent à sa production. Des cellules spécialisées de la sphère entérique détectent les variations glycémiques entre le sang artériel et la veine hépatoportale. Ces glucostats envoient des signaux nerveux via le nerf vague jusqu’au tronc cérébral qui relaie l’information vers l’hypothalamus. Ce dernier intègre également les messagers du sang circulant, comme les hormones et nutriments, puis adresse un nouveau message vers les tissus périphériques comme le foie, le pancréas, l’intestin, ou encore les vaisseaux sanguins. Ce réflexe métabolique est appelé anticipateur car il permet aux tissus d’être préparés en vue de l’utilisation des nutriments lors d’un repas. Les incrétines font partie des mécanismes importants impliqués. Ainsi, chez le sujet diabétique les thérapies fondées sur le GLP-1 sont particulièrement efficaces car elles prennent en compte de nombreuses cibles périphériques en activant cet arc réflexe métabolique. De nouvelles voies thérapeutiques sont ainsi envisageables qui permettraient une régulation fine de l’axe intestin-cerveau-tissus périphériques.
Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells
2004, Autonomic Neuroscience: Basic and Clinical
Citation Excerpt :
Therefore, the lack of laterality in the gene expression may imply the presence of extrahepatic recognition sites concerning different functions. For analogy, we previously reported that somatostatin-14 is sensed by both the hepatic (Nakabayashi et al., 1986, 1994, 1995) and the pancreatic (Nakabayashi et al., 1987) vagi through each site-specific particular apparatus containing nerve arbolizations which are able to bind somatostatin-14. As to CCK, although such a particular apparatus has not been discovered, afferent vagal fibers sensing the peptide are suggested to exist in close proximity to the releasing cells (Berthoud and Patterson, 1996).
We previously reported that afferent signals of the rat hepatic vagus increased upon intraportal appearance of insulinotropic hormone glucagon-like peptide-1(7-36) amide (GLP-1), but not glucose-dependent insulinotropic polypeptide (GIP). To obtain molecular evidence for the vagal chemoreception of GLP-1, the concept derived from those electrophysiological observations, receptor gene expressions of GLP-1 and GIP in the rat nodose ganglion were examined by means of reverse transcriptase-mediated polymerase chain reaction (RT-PCR) and Northern blot analysis. Gene expression of the GLP-1 receptor was clearly detected by both RT-PCR and Northern blot analysis. In situ hybridization study confirmed that the expression occurs in neuronal cells of the ganglion. As to the GIP receptor, RT-PCR amplified the gene transcript faintly though Northern blot analysis failed to detect any messages. However, semi-quantitative RT-PCR revealed that the ratio of the gene expression level of the GIP receptor to that of the GLP-1 receptor was less than 1:250, indicating that receptor gene expression of GIP is practically negligible in the ganglion. Additionally, an equal level of GLP-1 receptor gene expressions between left- and right-side ganglia was evidenced by semi-quantitative RT-PCR, implying possible extrahepatic occurrence of vagal GLP-1 reception in addition to the reception through the hepatic vagus (originating from the left-side ganglion). The present results offer, for the first time, the molecular basis for the vagal chemoreception of GLP-1 via its specific receptor.
The hepatic vagal reception of intraportal GLP-1 is via receptor different from the pancreatic GLP-1 receptor
2000, Journal of the Autonomic Nervous System
Citation Excerpt :
Taken together, those results mentioned above support the view that specific receptor-mediated system participates in the vagal reception of certain GEP hormones: the vagal nerve is able to recognize some of GEP hormones as far as the nerve has a specific receptor to each hormone (Nakabayashi, 1997). In this regard, it is intriguing whether expression of tGLP-1 receptor in the vagal nervous system is associated with the portal vein, as unique presentation of somatostatin receptor in the vein-associated neural body in the case of the hepatic vagal reception of somatostatin-14 (Nakabayashi et al., 1986; Nakabayashi et al., 1995; Nakabayashi, 1997). Further studies remain to be done.
Glucagon-like peptide-1 (7–36)amide (tGLP-1), a representative humoral incretin, released into the portal circulation in response to a meal ingestion, exerts insulinotropic action through binding to the tGLP-1 receptor known to be a single molecular form thus far. We previously reported that the hepatic vagal nerve is receptive to intraportal tGLP-1, but not to non-insulinotropic full-length GLP-1-(1–37), through a mechanism mediated by specific receptor to the hormone. In the present study, we aimed to examine how modification of the receptor function alters this neural reception of tGLP-1, by using the specific agonist, exendin-4, and the specific antagonist, exendin (9–39)amide, of the receptor at doses known to exert their effects on the insulinotropic action of tGLP-1. Intraportal injection of 0.2 or 4.0 pmol tGLP-1, a periphysiological and pharmacological dose, respectively, facilitated significantly the afferent impulse discharge rate of the hepatic vagus in anesthetized rats, as reported previously. However, unexpectedly, intraportal injection of exendin-4 at a dose of 0.2 or 4.0 pmol, or of even 40.0 pmol, did not facilitate the afferents at all. Moreover, intraportal injection of exendin (9–39)amide at 100 times or more molar dose to that of tGLP-1, either 5 min before or 10 min after injection of 0.2 or 4.0 pmol tGLP-1, failed to modify the tGLP-1-induced facilitation of the afferents. The present results suggest that the neural reception of tGLP-1 involves a receptor mechanism distinct from that in the well-known humoral insulinotropic action.
Neural monitoring system for circulating somatostatin in the hepatoportal area
1997, Nutrition
If a peptide hormone secreted from the gastroenteropancreatic (GEP) system is monitored by the hepatic vagal nerve, the nerve can signal the central nervous system and thereby exert control on its target organs. In this review, we offer a line of evidence for the hypothesis. When a physiological dose of somatostatin (SS), one of the GEP hormones, was injected into the rat portal vein, the spike discharge rate in the hepatic afferent vagus increased significantly. This SS-induced activation of the vagus was completely abolished by a prior administration of our monoclonal antibody to SS receptor into the portal vein. We further disclosed a morphological basis for this neural reception to SS in the hepatoportal area: the neural bodies, located beneath the endothelium of the rat portal vein, preferentially bound the exogenous SS injected intraportally as revealed immunohistologically. The bodies contained a structure of the nerve fiber arborizations resembling those of the afferent apparatus of Krause, on which the presence of SS receptor was confirmed histochemically using the anti-SS receptor antibody. These results provide a new insight into the receptor-mediated neural reception to GEP hormones in the hepatoportal area, implying the potential role of the reception in the GEP physiology.
The hepatic vagal nerve is receptive to incretin hormone glucagon-like peptide-1, but not to glucose-dependent insulinotropic polypeptide, in the portal vein
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To examine whether incretin hormones, truncated glucagon-like peptide-1 (tGLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are recognized by the hepatic vagal nerve, changes of the impulse discharge rate in the afferent vagus upon their intraportal administrations were measured in situ in rats anesthetized with urethan and chloralose. One-min injection of tGLP-1 at a periphysiological dose of 0.2 pmol or a pharmacological dose of 4.0 pmol, but not of the vehicle, significantly facilitated the hepatic vagal afferents. However, the injection of GIP at either a physiological dose of 0.2 pmol, a periphysiological dose of 4.0 pmol, or an even much larger dose of 40.0 pmol did not change the afferents at all. The present results indicate that the hepatic vagus specifically recognizes an intraportal appearance of tGLP-1 in the hepatoportal area, suggesting that the vagal monitoring system for intraportal levels of the incretin hormone operates on ingestion of a mixed meal.
Regulation of GH secretagogue receptor gene expression in the rat nodose ganglion
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Somatostatin receptor on the afferent nerve terminals in the rat hepatoportal area

Abstract

Neurosci. Lett.

J. Auton. Nerv. Syst.

An anterograde tracing study of the vagal innervation of rat liver, portal vein and biliary system

Anat. Embryol.

Pancreatic vagal nerve is receptive to somatostatin in rats

Am. J. Physiol.

Monoclonal antibodies to somatostatin receptor of rat brain

Hybridoma