Dopamine Receptors and TAAR1 Functional Interaction Patterns in the Duodenum Are Impaired in Gastrointestinal Disorders

Abstract

Currently, there is a growing amount of evidence for the involvement of dopamine receptors and the functionally related trace amine-associated receptor, TAAR1, in upper intestinal function. In the present study, we analyzed their expression in the duodenum using publicly accessible transcriptomic data. We revealed the expression of DRD1, DRD2, DRD4, DRD5, and TAAR1 genes in different available datasets. The results of the gene ontology (GO) enrichment analysis for DRD2 and especially TAAR1 co-expressed genes were consistent with the previously described localization of D2 and TAAR1 in enteric neurons and secretory cells, respectively. Considering that co-expressed genes are more likely to be involved in the same biological processes, we analyzed genes that are co-expressed with TAAR1, DRD2, DRD4, and DRD5 genes in healthy mucosa and duodenal samples from patients with functional dyspepsia (FD) or diabetes-associated gastrointestinal symptoms. Both pathological conditions showed a deregulation of co-expression patterns, with a high discrepancy between DRDs and TAAR1 co-expressed gene sets in normal tissues and patients' samples and a loss of these genes' functional similarity. Meanwhile, we discovered specific changes in co-expression patterns that may suggest the involvement of TAAR1 and D5 receptors in pathologic or compensatory processes in FD or diabetes accordingly. Despite our findings suggesting the possible role of TAAR1 and dopamine receptors in functional diseases of the upper intestine, underlying mechanisms need experimental exploration and validation.

Keywords: DRD2; DRD4; DRD5; TAAR1; diabetic gastroparesis; dopamine; duodenum; functional dyspepsia; trace amines.

Figure 1

Flowchart of the data search.

Figure 2

DRD (a) and TAAR (b) gene mRNA expression in the duodenum biopsy samples from healthy subjects (GSE151495, GSE169034, GSE189820, and GSE207243) and non-affected duodenal samples from patients with familial adenomatous polyposis (GSE94919, GSE189035).

Figure 3

Functional analysis of TAAR1 and DRD co-expressed genes in the healthy duodenal mucosa. Venn diagrams illustrate TAAR1 (a), DRD2 (b), DRD4 (c), and DRD4 (d) overlay in GSE151495 (marked by aquamarine green) and GSE169304 (marked by cyan blue). Gene ontology (GO) biological process (BP) enrichment analysis of genes co-expressed with TAAR1 (e) and DRD2 (f) in both datasets. GO biological process terms showed no appropriate enrichment in the DRD4 and DRD5 co-expressed gene cluster.

Figure 3

Functional analysis of TAAR1 and DRD co-expressed genes in the healthy duodenal mucosa. Venn diagrams illustrate TAAR1 (a), DRD2 (b), DRD4 (c), and DRD4 (d) overlay in GSE151495 (marked by aquamarine green) and GSE169304 (marked by cyan blue). Gene ontology (GO) biological process (BP) enrichment analysis of genes co-expressed with TAAR1 (e) and DRD2 (f) in both datasets. GO biological process terms showed no appropriate enrichment in the DRD4 and DRD5 co-expressed gene cluster.

Figure 4

Functional similarity of TAAR1 (a) and DRDs (b–d) co-expressed genes in duodenal mucosa from healthy donors and patients with functional dyspeptic disorders. Ctrl—healthy donors, FD—functional dyspepsia, RANDOM—random gene set, *—p < 0.05, ***—p < 0.001, ****—p < 0.0001, n.s.— non-significant.

Figure 5

Functional similarity of TRAA1 (a) and DRD (b–d) co-expressed genes in duodenal mucosa from healthy donors and patients with diabetes mellitus. Ctrl—healthy donors, DM—diabetes mellitus, RANDOM—random gene set, **—p < 0.01, ****—p < 0.0001, n.s.— non-significant.