Biological and Pharmacological Aspects of the NK1-Receptor

Abstract

The neurokinin 1 receptor (NK-1R) is the main receptor for the tachykinin family of peptides. Substance P (SP) is the major mammalian ligand and the one with the highest affinity. SP is associated with multiple processes: hematopoiesis, wound healing, microvasculature permeability, neurogenic inflammation, leukocyte trafficking, and cell survival. It is also considered a mitogen, and it has been associated with tumorigenesis and metastasis. Tachykinins and their receptors are widely expressed in various human systems such as the nervous, cardiovascular, genitourinary, and immune system. Particularly, NK-1R is found in the nervous system and in peripheral tissues and are involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation, and modulation of cell proliferation. It also acts as a neuromodulator contributing to brain homeostasis and to sensory neuronal transmission associated with depression, stress, anxiety, and emesis. NK-1R and SP are present in brain regions involved in the vomiting reflex (the nucleus tractus solitarius and the area postrema). This anatomical localization has led to the successful clinical development of antagonists against NK-1R in the treatment of chemotherapy-induced nausea and vomiting (CINV). The first of these antagonists, aprepitant (oral administration) and fosaprepitant (intravenous administration), are prescribed for high and moderate emesis.

Figure 1

Schematic model of the NK-1 receptor. (a) Complete isoform or long isoform-full length (NK1-FL) with 407 amino acids. It contains an extracellular N-terminus, seven transmembrane domains, three extracellular loops (E1, E2, and E3) and three intracellular loops (C1, C2, and C3), a possible C4 because of a Cys palmitoylation residue and an intracellular C-terminus. Asn14 and Asn18 are given as putative glycosylation sites. (b) Depiction of the truncated isoform with 311 amino acids, showing that this isoform has lost a part of the C-terminal end, and also the intracellular Ser/Thr residues responsible for internalization. Modified from [149].

Figure 2

Heterotrimeric G protein activation by GTP and consequent separation of subunits. Heterotrimeric G proteins have been grouped into four distinct families based on the G_α amino acid homologous sequence: G_s, G_i, G_q, and G_12/13. There are two major signaling pathways associated with G_αs and G_αq subunits and are mainly how NK-1 receptor signals [48, 50, 59]. The different signaling pathways activated by each subunit will be explained below. This figure was made using Servier Medical Art collection (http://creativecommons.org/licenses/by/3.0).

Figure 3

Some of the proposed signaling pathways activated by NK-R. (1) Gαs activation of AC catalyzes ATP to cyclic AMP (cAMP), which in turn binds to the regulatory subunits of the cAMP-dependent PKA. Usually PKA phosphorylates the CREB transcription factor. CREB binds to the cAMP response element (CRE) of a target gene and negatively affects the activation of NF-кB [49]. (2) Inhibition of the AC is performed by Pertussis toxin sensitive Gi protein [48]. Furthermore, Gi and βγ subunits enhance Erk1/2 activation after EGFR-mediated transactivation by Src protein [150]. (3) The SP binding to its receptor triggers a GTP-for-GDP exchange on Gα subunits, thus dissociating Gαq from Gβγ and subsequently activating downstream effectors such as PLC. This enzyme catalyzes the conversion of PIP2 in the second messenger IP3 and DAG, stimulating calcium mobilization and PKC activation, respectively [151]. Via nonreceptor protein kinases such as Src or Pyk2, PKC may activate the MAPK pathway but may also activate the Raf protein directly [77]. Another parallel mechanism that regulates MAPK may be developed during NK-1R internalization and its protein recruitment by β-arrestins [22, 78]. Although the mechanism is unknown, the Erk1/2 protein is also involved in NF-кB activation [84]. This Gαq subunit also mediates IL-6 production by activation of p38 MAPK [152]. (4) The Gα12/13 subunit is responsible for the activation of Rho/Rock which directly regulates the phosphorylation of the myosin light chain (MLC) [52]. Phosphorylation of this protein is associated with cytoskeletal reorganization and cell migration. The βγ dimer activates proteins such as Src, PI3K, and PLC [85]. This figure was made using Servier Medical Art collection (http://creativecommons.org/licenses/by/3.0).

Figure 4

NK-1 receptor distributed in the human body. NK-1R distribution across human tissues. This figure was made using Servier Medical Art collection (http://creativecommons.org/licenses/by/3.0).