Glucagon-Like Peptide-1 Receptor Controls Exocytosis in Chromaffin Cells by Increasing Full Fusion Events

Ayoze González-Santana,Elizabeth P Seward,José David Machado,Judith Estévez-Herrera,Ricardo Borges

doi:10.2139/ssrn.3659399

Ayoze González-Santana, Elizabeth P Seward + Show 3 more

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https://doi.org/10.2139/ssrn.3659399

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Abstract

Glucagon-like peptide-1 receptor (GLP-1R) agonists’ ability to increase insulin secretion and promote satiety have led to their development for the treatment of type 2 diabetes and obesity; while these beneficial effects have been attributed to receptors in the pancreas and hypothalamus, the function and importance of extra-pancreatic GLP-1Rs in other organ systems is not well understood despite the possibilities for targeting these receptors for other indications. We have analysed the contribution of GLP-1R to the secretory responses of adrenal medulla, a key player in stress responses. Exendin-4 (Ex-4), a synthetic analogue of GLP-1, increased the synthesis and the release of catecholamines (CA) by increasing cAMP production, without the participation of EPAC (Exchange Proteins Activated by cAMP). Ex-4 increased CA synthesis by promoting the activation of tyrosine hydroxylase (TH), and moreover increased the quantum size of exocytotic events by switching exocytosis from partial to full fusion. Our results give a strong support to the role of GLP-1 in the fine control of glycaemia and blood pressure by sympathetic tissues.

Highlights

Adrenal catecholamines (CAs) actively participate in the adaptive mechanisms used to restore body homeostasis in the body, especially in response to stress conditions such as hypoglycemia, cold, hypotension or fear (Goldstein, 2010)
The glucagon-like peptide-1 (7-36)amide (GLP-1) incretin receptor is expressed in chromaffin cells The expression of glucagon-like-peptide-1 receptor (GLP-1R) mRNA in bovine chromaffin cells was verified by RT-PCR (Figure S1) and its localization determined by immunocytochemistry and confocal microscopy
Chromaffin cells were positively identified by labeling with antibodies against tyrosine hydroxylase (TH); over 95% of cells in our cultures were labeled as TH positive

Summary

Introduction

Adrenal catecholamines (CAs) actively participate in the adaptive mechanisms used to restore body homeostasis in the body, especially in response to stress conditions such as hypoglycemia, cold, hypotension or fear (Goldstein, 2010). Chromaffin cells exert their control of body functions through the secretion of stored transmitters into the blood stream using regulated exocytosis. Stored within their large dense core vesicles ( called chromaffin granules) is a cocktail of small molecules, such as adrenaline, noradrenaline, and ATP, as well as bioactive peptides, granins, and enkephalins. Because of the neural origin of chromaffin cells, the nature of their secretory products, and the basic mechanisms of regulating exocytosis, chromaffin cells have been a widely used model for the study of the molecules that control vesicle fusion (Jahn et al, 2003; Neher, 2018; Neher and Marty, 1982; Wightman et al, 1991). Because the amount of secretory products released by each quantal fusion (partial versus full fusion) and its kinetics are subject to regulation (Alvarez de Toledo et al, 2018; Shin et al., 2018), this raises the possibility that even this late stage of exocytosis may be modulated by receptors

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