Neurotensin receptor type 1 is a protein that in humans is encoded by the NTSR1 gene. [5] [6] The neurotensin receptor is primarily responsible for mediating the effects of the neuropeptide neurotensin. [7]
Neurotensin receptor type 1 is a protein that in humans is encoded by the NTSR1 gene. [5] [6] The neurotensin receptor is primarily responsible for mediating the effects of the neuropeptide neurotensin. [7]
Neurotensin receptor type 1 (NTSR1) is a member of the class A G protein-coupled receptor (GPCR) superfamily, characterized by its canonical structure of seven transmembrane α-helices connected by extracellular and intracellular loops. [8] High-resolution crystal structures of NTSR1 have been determined in various functional states, including complexes with peptide agonists (such as the endogenous neurotensin fragment NTS8-13), non-peptide agonists, partial agonists, and antagonists, as well as in the ligand-free (apo) state. [9] [10]
The neurotensin binding pocket is located on the extracellular side of the receptor, where neurotensin binds in an extended conformation nearly perpendicular to the membrane, with the C-terminus oriented toward the receptor core. [10] Key interactions involve charged residues in the binding pocket and the C-terminal arginine of neurotensin, while the receptor’s activation is associated with conformational changes that propagate from the ligand-binding site through the transmembrane helices to the intracellular side. [9] The intracellular region of NTSR1 interacts with G proteins and β-arrestins, facilitating downstream signaling and receptor internalization; phosphorylation of specific intracellular sites is critical for stable β-arrestin binding. [11] Notably, the receptor also contains an amphipathic helix 8 following transmembrane helix 7, although its stability and presence may vary among different receptor states and constructs. [12]
Neurotensin receptor 1, also called NTSR1, belongs to the large superfamily of G-protein coupled receptors and is considered a class-A GPCR. NTSR1 mediates multiple biological processes through modulation by neurotensin, such as low blood pressure, high blood sugar, low body temperature, antinociception, anti-neuronal damage [13] and regulation of intestinal motility and secretion. [6]
SBI-553 has demonstrated allosteric modulation potential via Beta-arrestin-2 signaling. [14]
The anti-nociceptive properties of NTSR1 has been shown to be modulated by SBI-810, an analog of SBI-553 via inhibition of NMDA receptor activity as well as extracellular-regulated signal kinase signaling in spinal cord neurons. [14] SBI-810 outperformed gabapentin and oliceridine in reducing opioid-induced reduced conditioned place preference, guarding, and facial grimacing in mice, indicating superior mitigation of opioid withdrawal.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.