Proteolytic degradation of neuropeptide Y (NPY) from head to toe: Identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery.

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Proteolytic degradation of neuropeptide Y (NPY) from head to toe: Identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery. / Wagner, Leona; Wolf, Raik; Zeitschel, Ulrike; Rossner, Steffen; Petersén, Åsa; Leavitt, Blair R; Kästner, Florian; Rothermundt, Matthias; Gärtner, Ulf-Torsten; Gündel, Daniel; Schlenzig, Dagmar; Frerker, Nadine; Schade, Jutta; Manhart, Susanne; Rahfeld, Jens-Ulrich; Demuth, Hans-Ulrich; von Hörsten, Stephan.

In: Journal of Neurochemistry, Vol. 135, No. 5, 2015, p. 1019-1037.

Research output: Contribution to journalArticle

Harvard

Wagner, L, Wolf, R, Zeitschel, U, Rossner, S, Petersén, Å, Leavitt, BR, Kästner, F, Rothermundt, M, Gärtner, U-T, Gündel, D, Schlenzig, D, Frerker, N, Schade, J, Manhart, S, Rahfeld, J-U, Demuth, H-U & von Hörsten, S 2015, 'Proteolytic degradation of neuropeptide Y (NPY) from head to toe: Identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery.', Journal of Neurochemistry, vol. 135, no. 5, pp. 1019-1037. https://doi.org/10.1111/jnc.13378

APA

Wagner, L., Wolf, R., Zeitschel, U., Rossner, S., Petersén, Å., Leavitt, B. R., Kästner, F., Rothermundt, M., Gärtner, U-T., Gündel, D., Schlenzig, D., Frerker, N., Schade, J., Manhart, S., Rahfeld, J-U., Demuth, H-U., & von Hörsten, S. (2015). Proteolytic degradation of neuropeptide Y (NPY) from head to toe: Identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery. Journal of Neurochemistry, 135(5), 1019-1037. https://doi.org/10.1111/jnc.13378

CBE

Wagner L, Wolf R, Zeitschel U, Rossner S, Petersén Å, Leavitt BR, Kästner F, Rothermundt M, Gärtner U-T, Gündel D, Schlenzig D, Frerker N, Schade J, Manhart S, Rahfeld J-U, Demuth H-U, von Hörsten S. 2015. Proteolytic degradation of neuropeptide Y (NPY) from head to toe: Identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery. Journal of Neurochemistry. 135(5):1019-1037. https://doi.org/10.1111/jnc.13378

MLA

Vancouver

Author

Wagner, Leona ; Wolf, Raik ; Zeitschel, Ulrike ; Rossner, Steffen ; Petersén, Åsa ; Leavitt, Blair R ; Kästner, Florian ; Rothermundt, Matthias ; Gärtner, Ulf-Torsten ; Gündel, Daniel ; Schlenzig, Dagmar ; Frerker, Nadine ; Schade, Jutta ; Manhart, Susanne ; Rahfeld, Jens-Ulrich ; Demuth, Hans-Ulrich ; von Hörsten, Stephan. / Proteolytic degradation of neuropeptide Y (NPY) from head to toe: Identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery. In: Journal of Neurochemistry. 2015 ; Vol. 135, No. 5. pp. 1019-1037.

RIS

TY - JOUR

T1 - Proteolytic degradation of neuropeptide Y (NPY) from head to toe: Identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery.

AU - Wagner, Leona

AU - Wolf, Raik

AU - Zeitschel, Ulrike

AU - Rossner, Steffen

AU - Petersén, Åsa

AU - Leavitt, Blair R

AU - Kästner, Florian

AU - Rothermundt, Matthias

AU - Gärtner, Ulf-Torsten

AU - Gündel, Daniel

AU - Schlenzig, Dagmar

AU - Frerker, Nadine

AU - Schade, Jutta

AU - Manhart, Susanne

AU - Rahfeld, Jens-Ulrich

AU - Demuth, Hans-Ulrich

AU - von Hörsten, Stephan

PY - 2015

Y1 - 2015

N2 - The bioactivity of neuropeptide Y (NPY) is either N-terminally modulated with respect to receptor-selectivity by dipeptidyl-peptidase 4 (DP4)-like enzymes or proteolytic degraded by neprilysin or meprins, thereby abrogating signal transduction. However, neither the subcellular nor the compartmental differentiation of these regulatory mechanisms is fully understood. Using mass spectrometry, selective inhibitors and histochemistry, studies across various cell types, body fluids and tissues revealed that most frequently DP4-like enzymes, aminopeptidases P (AmpP), secreted meprin-A (Mep-A) and cathepsin D (CTSD) rapidly hydrolyze NPY, depending on the cell type and tissue under study. Novel degradation of NPY by cathepsins B, D, L, G, S and tissue kallikrein could also be identified. Expression of DP4, CTSD, and Mep-A at the median eminence indicates that the bioactivity of NPY is regulated by peptidases at the interphase between the periphery and the CNS. Detailed ex vivo studies on human sera and CSF samples recognized CTSD as the major NPY-cleaving enzyme in the CSF, whereas an additional C-terminal truncation by angiotensin-converting enzyme (ACE) could be detected in serum. The latter finding hints to potential drug interaction between antidiabetic DP4 inhibitors and anti-hypertensive ACE inhibitors, while it ablates suspected hypertensive side-effects of only antidiabetic DP4-inhibitors application. This article is protected by copyright. All rights reserved.

AB - The bioactivity of neuropeptide Y (NPY) is either N-terminally modulated with respect to receptor-selectivity by dipeptidyl-peptidase 4 (DP4)-like enzymes or proteolytic degraded by neprilysin or meprins, thereby abrogating signal transduction. However, neither the subcellular nor the compartmental differentiation of these regulatory mechanisms is fully understood. Using mass spectrometry, selective inhibitors and histochemistry, studies across various cell types, body fluids and tissues revealed that most frequently DP4-like enzymes, aminopeptidases P (AmpP), secreted meprin-A (Mep-A) and cathepsin D (CTSD) rapidly hydrolyze NPY, depending on the cell type and tissue under study. Novel degradation of NPY by cathepsins B, D, L, G, S and tissue kallikrein could also be identified. Expression of DP4, CTSD, and Mep-A at the median eminence indicates that the bioactivity of NPY is regulated by peptidases at the interphase between the periphery and the CNS. Detailed ex vivo studies on human sera and CSF samples recognized CTSD as the major NPY-cleaving enzyme in the CSF, whereas an additional C-terminal truncation by angiotensin-converting enzyme (ACE) could be detected in serum. The latter finding hints to potential drug interaction between antidiabetic DP4 inhibitors and anti-hypertensive ACE inhibitors, while it ablates suspected hypertensive side-effects of only antidiabetic DP4-inhibitors application. This article is protected by copyright. All rights reserved.

U2 - 10.1111/jnc.13378

DO - 10.1111/jnc.13378

M3 - Article

C2 - 26442809

VL - 135

SP - 1019

EP - 1037

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 1471-4159

IS - 5

ER -