Receptors, Volume 1, Issue 1 (December 2022) – 6 articles

Neurokinin-1 receptor (NK1R) signaling pathways play a crucial role in a number of biological processes in the eye. Specifically, in the ocular surface, their activity modulates epithelial integrity, inflammation, and generation of pain, while they have a role in visual processing in the retina. The NK1R is broadly expressed in the eye, in both ocular and non-ocular cells, such as leukocytes and neurons. In this review, we will discuss the roles of neurokinin-1 receptors and substance P (SP) in the physiopathology of eye disorders. Finally, we will review and highlight the therapeutic benefits of NK1R antagonists in the treatment of ocular diseases. Full article

The important role played by the substance P (SP)/neurokinin-1 receptor (NK-1R) system in cancer is reviewed: this includes tumor cell proliferation and migration, anti-apoptotic mechanisms, and angiogenesis. SP, through the NK-1R, behaves as a universal mitogen in cancer cells. The NK-1R is overexpressed in tumor cells and, in addition, affects the viability of cancer cells. NK-1R antagonists counteract all the previous actions mediated by SP through NK-1R. In a concentration-dependent manner, these antagonists promote tumor cell death by apoptosis. Therefore, NK-1R is a potential and promising therapeutic target for cancer treatment by using NK-1R antagonists (e.g., aprepitant) alone or in combination therapy with chemotherapy or radiotherapy. Full article

Substance P (SP), the first isolated neuropeptide, belongs to the family of tachykinin peptides and is the natural ligand of neurokinin-1 receptors (NK-1R), also named SP receptors. The undecapeptide activates the receptor after specifically binding to the protein and triggers intracellular signals leading to different biochemical events and subsequent physiological responses. This study reviews the main architectural features of this receptor, its interaction with natural and synthetic ligands, and the functional conformational states adopted after interacting with ligands and effector G proteins. The analysis of the main intracellular signaling pathways turned on by the activation of NK-1 receptors reveals the participation of different proteins supporting metabolic changes and genetic and epigenetic regulations. Furthermore, the analysis of receptor occupancy and receptor downregulation and internalization represents a complex and estimable field for basic and clinical research focused on the role of SP in physiopathology. Profound knowledge of the structural dynamics of NK-1R may help develop and assay new selective synthetic non-peptide antagonists as potential therapeutic agents applied to various pathologies and symptoms. Full article

Here, our data provide the first evidence for the existence of a previously unknown receptive system formed by novel DNA- and RNA-based receptors in eukaryotes. This system, named the TR-system, is capable of recognizing and generating a response to different environmental factors and has been shown to orchestrate major vital functions of fungi, mammalian cells, and plants. Recently, we discovered the existence of a similar regulatory system in prokaryotes. These DNA- and RNA-based receptors are localized outside of the membrane forming a type of a network around cells that responds to a variety of chemical, biological, and physical factors and enabled the TR-system to regulate major aspects of eukaryotic cell life as follows: growth, including reproduction and development of multicellular structures; sensitivity to temperature, geomagnetic field, UV, light, and hormones; interaction with viruses; gene expression, recognition and utilization of nutrients. The TR-system was also implicated in cell-memory formation and was determined to be responsible for its maintenance and the forgetting of preceding events. This system is the most distant receptive and regulatory system of the cell that regulates interactions with the outer environment and governs the functions of other receptor-mediated signaling pathways. Full article

(1) Background: In addition to the major phytocannabinoids, trans-Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD), the cannabis plant (Cannabis sativa L.) synthesizes over 120 additional cannabinoids that are known as minor cannabinoids. These minor cannabinoids have been proposed to act as agonists and antagonists at numerous targets including cannabinoid type 1 (CB₁) and type 2 (CB₂) receptors, transient receptor potential (TRP) channels and others. The goal of the present study was to determine the agonist effects of the minor cannabinoids: cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabitriol (CBT) and cannabidivarin (CBDV) at the CB₁ receptor. In addition, the CB₁ receptor antagonist effects of Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV) were compared with its isomer Δ⁸-tetrahydrocannabivarin (Δ⁸-THCV). (2) Methods: CB₁ receptor activity was monitored by measuring cannabinoid activation of G protein-gated inward rectifier K⁺ (GIRK) channels in AtT20 pituitary cells using a membrane potential-sensitive fluorescent dye assay. (3) Results: When compared to the CB₁ receptor full agonist WIN 55,212-2 and the partial agonist Δ⁹-THC, none of the minor cannabinoids caused a significant activation of G_i/GIRK channel signaling. However, Δ⁹-THCV and Δ⁸-THCV antagonized the effect of WIN 55,212-2 with half-maximal inhibitory concentrations (IC₅₀s) of 434 nM and 757 nM, respectively. Δ⁹-THCV antagonism of the CB₁ receptor was “ligand-dependent”; Δ⁹-THCV was more potent in inhibiting WIN 55,212-2 and 2-arachidonoylglycerol (2-AG) than Δ⁹-THC. (4) Conclusions: While none of the minor cannabinoids caused G_i/GIRK channel activation, Δ⁹-THCV antagonized the CB₁ receptor in an isomer- and ligand-dependent manner. Full article