Trace Amine-Associated Receptors and Monoamine-Mediated Regulation of Insulin Secretion in Pancreatic Islets

Abstract

Currently, metabolic syndrome treatment includes predominantly pharmacological symptom relief and complex lifestyle changes. Trace amines and their receptor systems modulate signaling pathways of dopamine, norepinephrine, and serotonin, which are involved in the pathogenesis of this disorder. Trace amine-associated receptor 1 (TAAR1) is expressed in endocrine organs, and it was revealed that TAAR1 may regulate insulin secretion in pancreatic islet β-cells. For instance, accumulating data demonstrate the positive effect of TAAR1 agonists on the dynamics of metabolic syndrome progression and MetS-associated disease development. The role of other TAARs (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) in the islet's function is much less studied. In this review, we summarize the evidence of TAARs' contribution to the metabolic syndrome pathogenesis and regulation of insulin secretion in pancreatic islets. Additionally, by the analysis of public transcriptomic data, we demonstrate that TAAR1 and other TAAR receptors are expressed in the pancreatic islets. We also explore associations between the expression of TAARs mRNA and other genes in studied samples and demonstrate the deregulation of TAARs' functional associations in patients with metabolic diseases compared to healthy donors.

Keywords: GPCR; TAAR; dopamine; insulin; pancreatic islets; trace amine-associated receptors; trace amines; transcriptomic.

Figure 1

The role of monoamine neurotransmitters in the insulin secretion of β-cells. (a) The main sources of monoamine neurotransmitters in pancreatic islets; all monoamine neurotransmitters may be synthesized in islets (1), the dopamine synthesis in islets needs L-DOPA which is realized from acini (2) or other sources, dopamine or norepinephrine are realized from the nerve endings (3), or acquired from the circulation (4). (b) Monoamines and their receptors are involved in the pancreatic islet hormone production. The activation effect is marked by red arrows, inhibition is marked by blue blunt arrows, and the dotted line indicates bioactive molecules’ release. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 2

The interactions between dopamine and insulin signaling. (a) The crosstalk between insulin signaling and dopamine signaling in the brain where the D1R and D2R receptors in the nucleus accumbens and VTA and dopamine receptors D1R in striatonigral pathway neurons regulate the reward system, which contributes to the normalization of eating behavior (1, 2, 3). The dopamine interaction with D2R receptor in the hypothalamus prevents prolactin production and consequent hyperinsulinemia (4). At the same time, insulin dualistically affects dopamine transmission by the activation of dopamine reuptake by DAT and prevention of dopamine degradation by MAO enzymes. (b) Intracellular interaction of insulin signaling and dopamine signaling resulting from common downstream targets, D2R inhibits Akt signaling by the β-arrestin-mediated signaling cascade (1) and activates MEK signaling (2) while D1R stimulation activates MEK via PKA-DARPP32 pathway (3) instead. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. DR1—dopamine receptor 1, DR2—dopamine receptor 2, IR—insulin receptor, IRS—insulin receptor substrate, SHC—Src homology 2 domain containing, PP2A—protein phosphatase 2A, PI3K—phosphatidylinositol 3-kinase, PDK1—pyruvate dehydrogenase kinase 1, GSK3—glycogen synthase kinase 3, MEK—mitogen-activated protein kinase kinase, ERK 1/2—extracellular signal-regulated kinase 1/2, PKA—protein kinase A, DARPP32—dopamine- and cAMP-regulated phosphoprotein with an apparent Mr of 32,000, PP1—protein phosphatase 1, STEP—striatal-enriched protein tyrosine phosphatase.

Figure 3

The associations between TAAR-mediated signaling and mechanisms involved in metabolic syndrome development. (1) TAAR1 expression was identified in brain structure involved in the reward system regulation which is involved in food consumption regulation; (2) TAAR1 was identified in the stomach epithelium, its activation on the D-cells leads to the somatostatin realizing, downregulation of ghrelin production, and reduces the feeling of hunger; (3) in the duodenum, TAAR1, TAAR2, and TAAR9 were identified; it is suggested that these receptors are involved in the regulation of neuroendocrine secretory cells that control appetite and glucose metabolism; (4) TAAR1 is expressed in β-cells and regulates insulin secretion, TAAR1 agonists could stimulate insulin secretion, but if TAAR1 dimerizes with ADRA2A, the effect of its activation on insulin secretion becomes inhibitory; (5) TAAR9 seems to be involved in the cholesterol metabolism regulation, but this regulatory mechanism is not clearly understood yet. Parts of the figure were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 4

TAARs and TAAR co-expressed gene clusters in pancreatic islets. (a) Expression levels of TAAR1, TAAR5, TAAR6, TAAR8, and TAAR9 in pancreatic islets isolated from healthy donors; (b) Venn diagram representing overlaps between TAAR1, TAAR5, TAAR6, TAAR8, and TAAR9 co-expressed gene clusters; (c) analysis of Gene Ontology (GO) enrichment of TAAR co-expressed gene clusters; (d) analysis of KEGG pathway enrichment of TAAR co-expressed gene clusters.

Figure 5

TAAR1 and TAAR1 co-expressed gene clusters in pancreatic islets isolated from healthy donors and patients with metabolic diseases. (a) Expression levels of TAAR1 healthy donors and patients with metabolic diseases; (b) functional similarity of TRAA1 co-expressed genes in islets isolated from healthy donors and patients with metabolic diseases. ND—non-diabetic (healthy donors), PreD—pre-diabetic, T2D—type 2 diabetes, T3cD—type 3c patients. *—p < 0.05, **—p < 0.01, ****—p < 0.001