Neurotensin receptor 1


Neurotensin receptor type 1 is a protein that in humans is encoded by the NTSR1 gene. The neurotensin receptor is primarily responsible for mediating the effects of the neuropeptide neurotensin.

Structure

Neurotensin receptor type 1 is a member of the class A G protein-coupled receptor superfamily, characterized by its canonical structure of seven transmembrane α-helices connected by extracellular and intracellular loops. High-resolution crystal structures of NTSR1 have been determined in various functional states, including complexes with peptide agonists, non-peptide agonists, partial agonists, and antagonists, as well as in the ligand-free state.
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. 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. 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. 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.

Function

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 and regulation of intestinal motility and secretion.

Neuromodulation

SBI-553 is an intracellular allosteric modulator that promotes β-arrestin recruitment but not canonical Gq signaling. SBI-553 exerts β-arrestin-dependent effects on rodent behavior.
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. 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.

Ligands

  • Neurotensin
  • ML314 – β-arrestin biased modulator
  • SBI-553 - β-arrestin biased modulator