The Neurokinin-1 Receptor: Structure Dynamics and Signaling

Abstract

Substance P (SP), the first isolated neuropeptide, belongs to the family of tachykinin peptides and is the natural ligand of neurokinin-1 receptors (NK-1R), also named SP receptors. The undecapeptide activates the receptor after specifically binding to the protein and triggers intracellular signals leading to different biochemical events and subsequent physiological responses. This study reviews the main architectural features of this receptor, its interaction with natural and synthetic ligands, and the functional conformational states adopted after interacting with ligands and effector G proteins. The analysis of the main intracellular signaling pathways turned on by the activation of NK-1 receptors reveals the participation of different proteins supporting metabolic changes and genetic and epigenetic regulations. Furthermore, the analysis of receptor occupancy and receptor downregulation and internalization represents a complex and estimable field for basic and clinical research focused on the role of SP in physiopathology. Profound knowledge of the structural dynamics of NK-1R may help develop and assay new selective synthetic non-peptide antagonists as potential therapeutic agents applied to various pathologies and symptoms.

The Repurposing of Non-Peptide Neurokinin-1 Receptor Antagonists as Antitumor Drugs: An Urgent Challenge for Aprepitant

“…The SP high-affinity receptor NK-1R is widely distributed throughout the body and can bind to hemokinin-1, endokinins, and neurokinins. For a recent review focused on the structural dynamics and signaling of NK-1R, see [23]. 2…”

“…These strategies will serve as a tool for designing and synthesizing new, selective, and more effective NK-1R antagonists. Moreover, targeting novel NK-1R-specific sites can lead to the discovery of drugs that can treat the numerous pathologies in which the SP/NK-1R system participates, such as cancer, pain, and depression [23]. This review will provide important information regarding the potential use of NK-1R antagonists as anticancer drugs, particularly Aprepitant in clinical practice as an antitumor drug.…”

Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families

“…Structural and functional studies of these membrane proteins have provided broad information on the structure–activity relationships that explain their role in cell function and their relevance in drug discovery with therapeutic applications [ 38 , 39 , 40 , 41 , 42 ]. Some recent research and reviews provided detailed and sound information on the structure and dynamics of NK-1R [ 43 , 44 , 45 , 46 ]. This section focuses on the architecture of the human NK-2R and NK 3R.…”

The Neurokinin-1 Receptor: A Promising Antitumor Target

“…This must be elucidated in future studies. A review focused on the structural dynamics and signaling cascades (e.g., mitogen-activated protein kinases (MAPK), hairy and enhancer of split 1 (Hes1)) of NK-1R has recently been published [71]. For example, Hes 1, a transcriptional blocker of the Notch signaling pathway, reduced the growth suppression of tumor cells when NK-1R was downregulated [72].…”

“…The design of NK-1R antagonists aims to obtain compounds with advantageous properties, such as efficacy, selectivity, bio-disponibility, lack of secondary or toxic effects, access to designated tissues, and manageable chemical properties. These properties make up the basis for drug synthesis, which also counts on the known characteristics of the destination binding pocket within the receptor structure [197]. One of the first potent non-peptide NK-1R antagonists reported (compound CP 96,345) has a quinuclidine structure with a benzhydryl group and a methoxy-benzylamine ring [198].…”