Neurotensin type 2 receptor (IPR003986)

Short name: NT2_rcpt

Overlapping homologous superfamilies


Family relationships


G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups [PMID: 12679517]. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence [PMID: 8170923]. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [PMID: 8170923, PMID: 8081729, PMID: 15914470, PMID: 18948278, PMID: 16753280]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice [PMID: 12679517]. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [PMID: 23020293].

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [PMID: 2111655, PMID: 2830256, PMID: 8386361].

Neurotensin is a 13-residue peptide transmitter, sharing significant similarity in its 6 C-terminal amino acids with several other neuropeptides, including neuromedin N. This region is responsible for the biological activity, the N-terminal portion having a modulatory role. Neurotensin is distributed throughout the central nervous system, with highest levels in the hypothalamus, amygdala and nucleus accumbens. It induces a variety of effects, including: analgesia, hypothermia and increased locomotor activity. It is also involved in regulation of dopamine pathways. In the periphery, neurotensin is found in endocrine cells of the small intestine, where it leads to secretion and smooth muscle contraction.

The existence of 2 neurotensin receptor subtypes, with differing affinities for neurotensin and differing sensitivities to the antihistamine levocabastine, was originally demonstrated by binding studies in rodent brain. Two neurotensin receptors (NT1 and NT2) with such properties have since been cloned and have been found to be G-protein-coupled receptor family members [PMID: 10390649].

The NT2 receptor was cloned from rat, mouse and human brains based on its similarity to the NT1 receptor. The receptor was found to be a low affinity, levocabastine sensitive receptor for neurotensin. Unlike the high affinity, NT1 receptor, NT2 is insensitive to guanosine triphosphate and has low sensitivity to sodium ions [PMID: 10390649]. Highest levels of expression of the receptor are found in the brain, in regions including: the olfactory system, cerebral and cerebellar cortices, hippocampus and hypothalamic nuclei. The distribution is distinct from that of the NT1 receptor, with only a few areas (diagonal band of Broca, medial septal nucleus and suprachiasmatic nuclei) expressing both receptor subtypes. The receptor has also been found at lower levels in the kidney, uterus, heart and lung [PMID: 9851594]. Activation of the NT2 receptor by non-peptide agonists suggests that the receptor can couple to phospholipase C, phospholipase A2 and MAP kinase. A functional response to neurotensin, however, is weak [PMID: 9627096] or absent, and neurotensin appears to act as an antagonist of the receptor [PMID: 9851594]. It has been suggested that a substance other than neurotensin may act as the natural ligand for this receptor.

GO terms

Biological Process

GO:0007186 G protein-coupled receptor signaling pathway

Molecular Function

GO:0016492 G protein-coupled neurotensin receptor activity

Cellular Component

GO:0016021 integral component of membrane

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.