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Hemokinin 1 is a full agonist at the substance P receptor

Nature Immunology volume 2, page 1088 (2001)Cite this article

In the initial report, HK-1 was shown to have proliferative and anti-apoptotic actions on B220+ cells in vitro1. Effective concentrations were in the high micromolar range and, because similar activity could not be demonstrated for substance P, the authors postulated the presence of a distinct receptor that is selective for HK-1. However, in nanomolar concentrations, substance P can support hematopoiesis of highly purified human peripheral blood mononuclear cells in the absence of exogenous growth factors2. We hypothesized that HK-1 might be more resistant to proteolytic inactivation based on the substitution of tyrosine for phenylalanine at position 8. As a result, HK-1 would be predicted to show biological activity at lower concentrations. As inhibition of neprilysin is critical to maintaining substance P activity3,4, we compared the degradation rates of substance P and HK-1 by purified neprilysin. Our data show that HK-1 is degraded by this enzyme with kinetics approximately half that of substance P, supporting the stabilizing effect of the amino acid substitution and increased apparent biological activity of HK-1.

The report by Zhang et al. also indicated a 90% reduction reduction in pre-B cells in bone marrow and a ∼70% reduction in immature B cells in spleens of mice treated with a NK-1R antagonist1. We generated NK-1R−/− mice on a BALB/c background5 and found that the deficiency in NK-1 receptor was also associated with reductions in these cell populations, but only by ∼25%. The mouse strain used was the F1 cross of C57BL/6 with DBA2, which potentially explains the difference in magnitude of the changes in cell populations1.

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Figure 1: Competition binding of substance P and HK-1 on 293T cells transfected with the human NK-1 receptor.

References

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Authors and Affiliations

  1. Ina Sue Perlmutter Laboratory and Department of Pediatrics, Children's Hospital, Boston, 02115, MA, USA

    Olivier Morteau, Bao Lu, Craig Gerard & Norma P. Gerard

  2. Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 02115, MA, USA

    Norma P. Gerard

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  1. Olivier Morteau
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  2. Bao Lu
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  3. Craig Gerard
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  4. Norma P. Gerard
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Morteau, O., Lu, B., Gerard, C. et al. Hemokinin 1 is a full agonist at the substance P receptor. Nat Immunol 2, 1088 (2001). https://doi.org/10.1038/ni1201-1088

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