Hemokinin 1 (human)

PPT-C encoded hemokinin-1(hHK-1) of Homo sapiens (TGKASQFFGLM) is a structurally distinct neuropeptide among the tachykinin family that participate in the NK-1 receptor downstream signaling processes. Subsequently, signal transduction leads to execution of various effector functions which includes aging, immunological, and central nervous system (CNS) regulatory actions. However the conformational pattern of ligand receptor binding is unclear. The three-dimensional structure of the hemokinin-1 in aqueous and micellar environment has been studied by one and two-dimensional proton nuclear magnetic resonance (2D 1H-NMR spectroscopy) and distance geometry calculations. Data shows that hemokinin-1 was unstructured in aqueous environment; anionic detergent SDS induces α-helix formation. Proton NMR assignments have been carried out with the aid of correlation spectroscopy (gradient-COSY and TOCSY) and nuclear Overhauser effect spectroscopy (NOESY and ROESY) experiments. The inter proton distances and dihedral angle constraints obtained from the NMR data have been used in torsion angle dynamics algorithm for NMR applications (CYANA) to generate a family of structures, which have been refined using restrained energy minimization and dynamics.

Mast cells are critical players in allergic reactions, but they have also been shown to be important in immunity and recently also in inflammatory diseases, especially asthma. Migraines are episodic, typically unilateral, throbbing headaches that occur more frequently in patients with allergy and asthma implying involvement of meningeal and/or brain mast cells. These mast cells are located perivascularly, in close association with neurons especially in the dura, where they can be activated following trigeminal nerve, as well as cervical or sphenopalatine ganglion stimulation. Neuropeptides such as calcitonin gene-related peptide (CGRP), hemokinin A, neurotensin (NT), pituitary adenylate cyclase activating peptide (PACAP), and substance P (SP) activate mast cells leading to secretion of vasoactive, pro-inflammatory, and neurosensitizing mediators, thereby contributing to migraine pathogenesis. Brain mast cells can also secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), selectively in response to corticotropin-releasing hormone (CRH), a mediator of stress which is known to precipitate or exacerbate migraines.

Granulomas are chronic inflammations that prevent spread of poorly controllable infectious agents. The gut lumen contains enteric organisms that are excluded from the host by leukocytes located in the intestinal lining. Physiological intestinal inflammation and granulomas share some similarities. Both function to confine, but not necessarily abolish potentially harmful factors. Also, both are subject to intense immune regulation to avoid unnecessary tissue injury. Substance P and its natural analog hemokinin are produced at these sites of inflammation and are important components of this regulatory process. They act through a shared receptor (NK-1) expressed on T cells, macrophages, dendritic cells and probably other cell types. One of their functions is to enhance IFN-gamma production and amplify the Th1 response. The NK-1 receptor is an important target for immune regulation. Several Th1 cytokines and T cell antigen receptor (TCR) activation induce NK-1 receptor expression on T cells, while IL-10 and TGF-beta block receptor display. Macrophages also have an inducible NK-1 receptor. Various types of immune cells can make substance P and hemokinin, whose syntheses also are subject to immunoregulation.