Role of G protein-coupled receptors-microRNA interactions in gastrointestinal pathophysiology

Abstract

G protein-coupled receptors (GPCRs) make up the largest transmembrane receptor superfamily in the human genome and are expressed in nearly all gastrointestinal cell types. Coupling of GPCRs and their respective ligands activates various phosphotransferases in the cytoplasm, and, thus, activation of GPCR signaling in intestine regulates many cellular and physiological processes. Studies in microRNAs (miRNAs) demonstrate that they represent critical epigenetic regulators of different pathophysiological responses in different organs and cell types in humans and animals. Here, we reviewed recent research on GPCR-miRNA interactions related to gastrointestinal pathophysiology, such as inflammatory bowel diseases, irritable bowel syndrome, and gastrointestinal cancers. Given that the presence of different types of cells in the gastrointestinal tract suggests the importance of cell-cell interactions in maintaining gastrointestinal homeostasis, we also discuss how GPCR-miRNA interactions regulate gene expression at the cellular level and subsequently modulate gastrointestinal pathophysiology through molecular regulatory circuits and cell-cell interactions. These studies helped identify novel molecular pathways leading to the discovery of potential biomarkers for gastrointestinal diseases.

Keywords: epigenetics; inflammation; inflammatory bowel disease; intestinal epithelial cells; microribonucleic acid; neuropeptides.

Fig. 1.

A representative diagram of possible G protein-coupled receptor (GPCR)-microRNA (miRNA) interactions at the cellular level. miRNA transcription is initiated by either external stimuli (a) or GPCR activation (b). Primary miRNAs (pri-miRNAs) are transcribed in nucleus (c) and exported to cytoplasm as smaller-hairpin RNAs of ∼70 nucleotides (pre-miRNAs) (d). miRNAs, together with Argonaute protein family (AGO) proteins, then bind to their corresponding complementary sequence in the 3′-untranslated region (UTR) of their target mRNA transcript, in which the target mRNA transcripts will be destabilized or their translation will be inhibited. Subsequently, the expression of target proteins is reduced. The above process affects the expression of proteins that are downstream of GPCR signaling activation (e), components that facilitate GPCR signaling activation (f), or GPCR itself (g).

Fig. 2.

Representative diagram showing the physiological role of NK₁ and neurotensin-1 (NTS₁) receptor interactions with miRNAs on cellular and tissue levels. In colonic epithelial cells, substance P (SP)/NK₁ receptor coupling increases miR-221–5p expression through NF-κB and c-Jun NH₂-terminal kinase (JNK) activation, leading to a reduction in the expression of interleukin-6 receptor (IL6R), the downstream target of miR-221–5p. On the other hand, NTS/NTS₁ receptor coupling activates hypoxia-inducible factor-1α (HIF-1α)-regulated miR-210 transcription and reduces the expression of ephrin A3 (EFNA3), a direct target of miR-210, whereas NTS/NTS₁ receptor activation alleviates inhibition of miR-133α expression by zinc finger E-box-binding homeobox 1 and therefore reduces aftiphilin (AFTPH) levels. Our studies show that NTS/NTS₁ receptor-associated EFNA3 reduction contributes to increased angiogenesis, whereas NTS/NTS₁ receptor-associated AFTPH reduction promotes NTS₁ receptor recycling in vitro. Importantly, intracolonic administration of antisense miR-221–5p exacerbates experimental colitis development, whereas intracolonic administration of antisense miR-133α and antisense miR-210 ameliorates 2,4,6-trinitrobenzenesulfonic acid-induced colonic inflammation by reducing proinflammatory cytokine production and attenuating development of colitic phenotype.