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Neuropeptide Y receptor interactions regulate its mitogenic activity.

ABSTRACT: 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.

SUBMITTER: Czarnecka M

PROVIDER: S-EPMC6532649 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Neuropeptide Y receptor interactions regulate its mitogenic activity.

Czarnecka Magdalena M Lu Congyi C Pons Jennifer J Maheswaran Induja I Ciborowski Pawel P Zhang Lihua L Cheema Amrita A Kitlinska Joanna J

Neuropeptides 20181127

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 peptid ...[more]

PMID: 30503694

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Project description:The sigma 1 receptor (?1R) and the mu-opioid receptor (MOR) regulate the transient receptor potential (TRP) V1 calcium channel. A series of proteins are involved in the cross-regulation between MORs and calcium channels like the glutamate N-methyl-D-aspartate receptor (NMDAR), including the histidine triad nucleotide-binding protein 1 (HINT1), calmodulin (CaM), and the ?1R. Thus, we assessed whether similar mechanisms also apply to the neural TRP ankyrin member 1 (TRPA1), TRP vanilloid member 1 (TRPV1), and TRP melastatin member 8 (TRPM8). Our results indicate that ?1R and CaM bound directly to cytosolic regions of these TRPs, and this binding increased in the presence of calcium. By contrast, the association of HINT1 with these TRPs was moderately dependent on calcium. The ?1R always competed with CaM for binding to the TRPs, except for its binding to the TRPA1 C-terminal where ?1R binding cooperated with that of CaM. However, ?1R dampened HINT1 binding to the TRPA1 N-terminal. When the effect of ?1R ligands was addressed, the ?1R agonists PRE084 and pregnenolone sulfate enhanced the association of the ?1R with the TRPM8 N-terminal and TRPV1 C-terminal in the presence of physiological calcium, as seen for the ?1R-NMDAR interactions. However, these agonists dampened ?1R binding to the TRPA1 and TRPV1 N-terminal domains, and also to the TRPA1 C-terminal, as seen for ?1R-binding immunoglobulin protein (BiP) interactions in the endoplasmic reticulum (ER). By contrast, the ?1R antagonists progesterone and S1RA reduced the association of ?1R with TRPA1 and TRPV1 C-terminal regions, as seen for the ?1R-NMDAR interactions. Conversely, they enhanced the ?1R interaction with the TRPA1 N-terminal, as seen for ?1R-BiP interactions, whereas they barely affected the association of ?1R with the TRPV1 N-terminal. Thus, depending on the calcium channel and the cytosolic region examined, the ?1R agonists pregnenolone sulfate and PRE084 opposed or collaborated with the ?1R antagonists progesterone and S1RA to disrupt or promote such interactions. Through the use of cloned cytosolic regions of selected TRP calcium channels, we were able to demonstrate that ?1R ligands exhibit biased activity to regulate particular ?1R interactions with other proteins. Since ?1Rs are implicated in essential physiological processes, exploiting such ligand biases may represent a means to develop more selective and efficacious pharmacological interventions.

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Neuropeptide Y receptor interactions regulate its mitogenic activity.

Publications

Neuropeptide Y receptor interactions regulate its mitogenic activity.

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