Truncation of neurokinin-1 receptor—Negative regulation of substance P signaling

Abstract

Substance P (SP) is a tachykinin peptide, which triggers intracellular signaling in the nervous and immune systems, as well as, other local and systemic events. The interaction between SP and its receptor, neurokinin-1 receptor (NK1R), results in major downstream cellular actions, which include changes in calcium fluxes, ERK, and p21-activated kinase phosphorylation and NFκB activation. Two naturally occurring variants of the NK1R, the full-length, 407 aa receptor (NK1R-F) and the truncated, 311 aa isoform (NK1R-T), mediate the actions of SP. Receptor truncation partially disrupts signaling motifs of the carboxyl tail, a critical site for mediating NK1R signaling, resulting in a "less-efficient" receptor. Although NK1R-F is the predominant isoform in the central and peripheral nervous systems, NK1R-T is expressed in several tissues and cells, which include monocytes, NK cells, and T-cells. The SP binding domain is not affected by truncation and this site is identical in both NK1R receptor isoforms. However, while cells expressing NK1R-F respond to nanomolar concentrations of SP, monocyte and macrophage activation, mediated through NK1R-T, requires micromolar concentrations of SP in order to elicit signaling responses. Elevated plasma levels of SP are associated with increased inflammatory responses and NK1R antagonists reduce inflammation and cytokine production in vivo. This mini review presents and discusses the novel hypothesis that the expression of NK1R-T on immune system cells prevents immune activation in a milieu, which usually contains low concentrations of SP and, thus, maintains immune homeostasis. In contrast, in the activated neuronal microenvironment, when SP levels reach the threshold at tissue sites, SP promotes immune activation and modulates monocyte/macrophage polarization.

Identification of the Neurokinin-1 Receptor as Targetable Stratification Factor for Drug Repurposing in Pancreatic Cancer

“…A number of studies has already investigated splice variant subordinate differences between normal and malignant tissues, proving the homogenic and tissue specific presence of either one of the two isoforms [ 14 , 20 , 32 ]. Whereas the full transcript was commonly identified in areas of the central and peripheral nervous system, the truncated form is expressed in several tissues and cells [ 33 ]. We hypothesized PDAC cells to predominantly express NK1R-tr over the full-length version, which was confirmed through RT-qPCR analysis, while also providing proof for the absence of NK1R-fl in all tested PDAC cells.…”

A Novel Mechanism of Endoplasmic Reticulum Stress‐ and c‐Myc‐Degradation‐Mediated Therapeutic Benefits of Antineurokinin‐1 Receptor Drugs in Colorectal Cancer

“…ERK signaling is a major pathway downstream of NK‐1R activation [ 14 ] and regulates c‐Myc protein stability. [ 15 ] Indeed, treatment with either SR140333 ( Figure 3 A ) or aprepitant (Appendix A1 and Figure S5 , Supporting Information) resulted in an acute reduction in ERK1/2 phosphorylation, along with diminished c‐Myc protein expression in HCT116 and SW620 cells.…”

Neurokinin-1 Receptor Signaling Is Required for Efficient Ca2+ Flux in T-Cell-Receptor-Activated T Cells

“…Two isoforms of the NK1R have been described, the f-NK1R and the C-terminus-truncated (t-NK1R) variants (Lai et al, 2006). Whereas f-NK1R-signaling promotes binding of the f-NK1R to G aq/11 subunits and causes increase in cytosolic Ca 2+ , agonistic binding to the t-NK1R does not (Spitsin et al, 2018;Tuluc et al, 2009). Although the NK1R is expressed in T cells, it is unknown if both isoforms are present in T cells and how their level of expression changes during TCR-activation.…”