Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation

Abstract

The G protein-coupled receptor (GPCR), neurokinin-1 receptor (NK1R), and its preferred ligand, substance P (SP), are reviewed in relationship to the immune system and selected infections. NK1R and SP are ubiquitous throughout the animal kingdom. This important pathway has unique functions in numerous cells and tissues. The interaction of SP with its preferred receptor, NK1R, leads to the activation of nuclear factor-kappa B (NF-κB) and proinflammatory cytokines. NK1R has two isoforms, both a full-length and a truncated form. These isoforms have different functional significances and differ in cell signaling capability. The proinflammatory signals modulated by SP are important in bacterial, viral, fungal, and parasitic diseases, as well as in immune system function. The SP-NK1R system is a major class 1, rhodopsin-like GPCR ligand-receptor interaction.

Figure 1

Schematic model of the NK-1 receptor membrane topography. The rat NK-1 receptor contains an extracellular N-terminus, seven putative hydrophobic membrane-spanning domains, intervening extracellular loops (E1, E2, and E3) and intracellular loops (C1, C2, C3 and a possible C4 due to Cys residue palmitoylation) and an intracellular C-terminus. Asn14 and Asn18 are indicated as putative sites of Asn-glycosylation. A disulfide bond exists between Cys105 and Cys180, connecting the first and second extracellular loops. [Orignally published in Bremer & Leeman (2010). Reproduced with permission.]

Figure 2

Proposed signal transduction pathways following NK-1 receptor activation. Functional interaction of substance P with the NK-1 receptor stimulates NK-1 receptor-mediated CDP/CTP exchange on the G_aq subunit and the subsequent activation of PLC β (phospholipase C β). The two intracellular second messengers, IP₃ (inositol 1,4,6-triphosphate) and DAG (diacylgylcerol), then stimulate the mobilization of intracellular Ca²⁺ and the activation of PKC (protein kinase C), respectively. Current interest is focusing on the possible gene regulatory effects of G protein-coupled receptor activation mediated by the G_ργ subunits. [Orignally published in Bremer & Leeman (2010). Reproduced with permission.]