TY - JOUR
T1 - Neuropeptide Y receptor interactions regulate its mitogenic activity
AU - Czarnecka, Magdalena
AU - Lu, Congyi
AU - Pons, Jennifer
AU - Maheswaran, Induja
AU - Ciborowski, Pawel
AU - Zhang, Lihua
AU - Cheema, Amrita
AU - Kitlinska, Joanna
N1 - Funding Information:
The authors thank Dr. Jason Tilan for critical reading of the manuscript. This work was supported by National Institutes of Health (NIH) grants: 1RO1CA123211 , 1R03CA178809 , R01CA197964 and 1R21CA198698 , as well as grants from Sunbeam Foundation and Children's Cancer Foundation to JK. MS analysis and microscopy were performed at the Georgetown-Lombardi Comprehensive Cancer Center's Proteomics and Metabolomics Shared Resource (PMSR) and the Microscopy & Imaging Shared Resource (MISR), respectively, both supported by NIH/NCI grant P30-CA051008 . The funding agencies were not involved in study design, data analysis, writing and publication decisions.
Funding Information:
The authors thank Dr. Jason Tilan for critical reading of the manuscript. This work was supported by National Institutes of Health (NIH) grants: 1RO1CA123211, 1R03CA178809, R01CA197964 and 1R21CA198698, as well as grants from Sunbeam Foundation and Children's Cancer Foundation to JK. MS analysis and microscopy were performed at the Georgetown-Lombardi Comprehensive Cancer Center's Proteomics and Metabolomics Shared Resource (PMSR) and the Microscopy & Imaging Shared Resource (MISR), respectively, both supported by NIH/NCI grant P30-CA051008. The funding agencies were not involved in study design, data analysis, writing and publication decisions.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2019/2
Y1 - 2019/2
N2 - Neuropeptide Y (NPY) is a multifunctional neurotransmitter acting via G protein-coupled receptors - Y1R, Y2R and Y5R. NPY activities, such as its proliferative effects, are mediated by multiple receptors, which have the ability to dimerize. However, the role of this receptor interplay in NPY functions remains unclear. The goal of the current study was to identify NPY receptor interactions, focusing on the ligand-binding fraction, and determine their impact on the mitogenic activity of the peptide. Y1R, Y2R and Y5R expressed in CHO-K1 cells formed homodimers detectable on the cell surface by cross-linking. Moreover, Y1R and Y5R heterodimerized, while no Y2R/Y5R heterodimers were detected. Nevertheless, Y5R failed to block internalization of its cognate receptor in both Y1R/Y5R and Y2R/Y5R transfectants, indicating Y5R transactivation upon stimulation of the co-expressed receptor. These receptor interactions correlated with an augmented mitogenic response to NPY. In Y1R/Y5R and Y2R/Y5R transfectants, the proliferative response started at picomolar NPY concentrations, while nanomolar concentrations were needed to trigger proliferation in cells transfected with single receptors. Thus, our data identify direct and indirect heterotypic NPY receptor interactions as the mechanism amplifying its activity. Understanding these processes is crucial for the design of treatments targeting the NPY system.
AB - Neuropeptide Y (NPY) is a multifunctional neurotransmitter acting via G protein-coupled receptors - Y1R, Y2R and Y5R. NPY activities, such as its proliferative effects, are mediated by multiple receptors, which have the ability to dimerize. However, the role of this receptor interplay in NPY functions remains unclear. The goal of the current study was to identify NPY receptor interactions, focusing on the ligand-binding fraction, and determine their impact on the mitogenic activity of the peptide. Y1R, Y2R and Y5R expressed in CHO-K1 cells formed homodimers detectable on the cell surface by cross-linking. Moreover, Y1R and Y5R heterodimerized, while no Y2R/Y5R heterodimers were detected. Nevertheless, Y5R failed to block internalization of its cognate receptor in both Y1R/Y5R and Y2R/Y5R transfectants, indicating Y5R transactivation upon stimulation of the co-expressed receptor. These receptor interactions correlated with an augmented mitogenic response to NPY. In Y1R/Y5R and Y2R/Y5R transfectants, the proliferative response started at picomolar NPY concentrations, while nanomolar concentrations were needed to trigger proliferation in cells transfected with single receptors. Thus, our data identify direct and indirect heterotypic NPY receptor interactions as the mechanism amplifying its activity. Understanding these processes is crucial for the design of treatments targeting the NPY system.
KW - G protein-coupled receptors
KW - Heterodimerization
KW - Homodimerization
KW - Neuropeptide Y
KW - Proliferation
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U2 - 10.1016/j.npep.2018.11.008
DO - 10.1016/j.npep.2018.11.008
M3 - Article
C2 - 30503694
AN - SCOPUS:85057410066
SN - 0143-4179
VL - 73
SP - 11
EP - 24
JO - Neuropeptides
JF - Neuropeptides
ER -