Serotonin (5-HT) receptor 2b activation augments glucose-stimulated insulin secretion in human and mouse islets of Langerhans

Abstract

Aims/hypothesis The G q -coupled 5-hydroxytryptamine 2B (5-HT 2B ) receptor is known to regulate the proliferation of islet beta cells during pregnancy. However, the role of serotonin in the control of insulin release is still controversial. The aim of the present study was to explore the role of the 5-HT 2B receptor in the regulation of insulin secretion in mouse and human islets, as well as in clonal INS-1(832/13) cells. Methods Expression of HTR2B mRNA and 5-HT 2B protein was examined with quantitative real-time PCR, RNA sequencing and immunohistochemistry. α-Methyl serotonin maleate salt (AMS), a serotonin receptor agonist, was employed for robust 5-HT 2B receptor activation. Htr2b was silenced with small interfering RNA in INS-1(832/13) cells. Insulin secretion, Ca 2+ response and oxygen consumption rate were determined. Results Immunohistochemistry revealed that 5-HT 2B is expressed in human and mouse islet beta cells. Activation of 5-HT 2B receptors by AMS enhanced glucose-stimulated insulin secretion (GSIS) in human and mouse islets as well as in INS-1(832/13) cells. Silencing Htr2b in INS-1(832/13) cells led to a 30% reduction in GSIS. 5-HT 2B receptor activation produced robust, regular and sustained Ca 2+ oscillations in mouse islets with an increase in both peak distance (period) and time in the active phase as compared with control. Enhanced insulin secretion and Ca 2+ changes induced by AMS coincided with an increase in oxygen consumption in INS-1(832/13) cells. Conclusions/interpretation Activation of 5-HT 2B receptors stimulates GSIS in beta cells by triggering downstream changes in cellular Ca 2+ flux that enhance mitochondrial metabolism. Our findings suggest that serotonin and the 5-HT 2B receptor stimulate insulin release.

Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells

“…Genes encoding members of the Gα i -linked receptor 5-HT 1 family, as well as 5-HT 5A and 5-HT 3E were expressed in human islets (Figure 4A). 5-HT 2B and 5-HT 3A receptor genes were expressed at lower levels [Figure S5; for 5-HT 2B receptors in human and mouse islet beta cells also see (Bennet et al, 2016; Blodgett et al, 2015)]. To localize the receptors expressed at higher levels (5-HT 1 family members, 5-HT 5A , and 5-HT 3E ) to particular cell types within the islet we performed immunostaining on human pancreatic sections.…”

“…Serotonin has been investigated extensively as an autocrine signal regulating beta cell function and proliferation (Bennet et al, 2016; Goyvaerts et al, 2016; Kim et al, 2010; Kim et al, 2015; Ohara-Imaizumi et al, 2013). By contrast, the effects of serotonin on hormone secretion from other islet endocrine cells have not been systematically investigated.…”

“…Recent studies renewed interest in serotonin by showing that, during heightened metabolic demand such as pregnancy or high-fat diet feeding, serotonin is produced in the islet and required to maintain glucose homeostasis (Goyvaerts et al, 2015; Kim et al, 2010; Kim et al, 2015; Schraenen et al, 2010). To this end, beta cells increase synthesis of serotonin and secrete it to enhance insulin secretion and stimulate beta cell proliferation via 5-HT 2B and 5-HT 3 receptors (Bennet et al, 2016; Kim et al, 2010; Kim et al, 2015; Ohara-Imaizumi et al, 2013). Serotonin also promotes insulin granule exocytosis in a receptor-independent manner through serotonylation of small GTPases of Rab family (Paulmann et al, 2009).…”

Energy Homeostasis by the Peripheral Serotonergic System

“…In addition, other research has determined that Htr2b, G-protein-coupled receptor, also has an impact on GSIS [16]. In human and mouse islets, Htr2b is expressed in β cells but not in α cells.…”

5-HT2Bserotonin receptor agonist BW723C86 shapes the macrophage gene profile via AhR and impairs monocyte-to-osteoclast differentiation

“…Since some of these 5-HT 2B -targeting drugs induce VHD, their use is restricted, and novel potential drugs are commonly screened for 5-HT 2B agonist activity. 5-HT 2B engagement enhances proliferation of numerous cell types 9,[58][59][60][61][62][63][64][65][66][67] via Gαq and Src phosphorylation, and through production of growth factors like insulin 68 , TGFβ1, CTGF, FGF2 45,60 and TGFα 69 . In macrophages, 5-HT 2B prevents mononuclear phagocyte degeneration in amyotrophic lateral sclerosis 70 , and Htr2b -/microglia exhibits a mild inflammatory state 71 , which is in line with the ability of 5-HT 2B antagonist SB204741 to impair the acquisition of human macrophage polarization-specific genes 40 and TGFβ1 expression by mouse Kupffer cells 45 .…”