Are Hormones from the Neuropeptide Y Family Recognized by Their Receptors from the Membrane‐Bound State?

Abstract

Hormones and many other neurotransmitters, growth factors, odorant molecules, and light all present stimuli for a class of membrane-anchored receptors called G protein-coupled receptors (GPCRs). The GPCRs are the largest family of cell-surface receptors involved in signal transduction. About 1% of all known genes of Drosophila and more than 5% of the genes of Caenorhabditis elegans encode GPCRs. In addition, more than 50% of current therapeutic agents on the market target these receptors. When the enormous biological and pharmaceutical importance of these receptors is considered, it is surprising how little is known about the mechanism with which these receptors recognize their natural ligands. In this review we present a structural approach, utilizing techniques of high-resolution NMR spectroscopy, to address the question of whether peptides from the neuropeptide Y family of neurohormones are recognized directly from solution or from the membrane-bound state. In our studies we discovered that the structures of the membrane-bound species are better correlated to the pharmacological properties of these peptides than the solution structures are. These findings are supported by the observation that many biophysical properties of these peptides seem to be optimized for membrane binding. We finally present a scenario of possible events during receptor recognition.

Micellar nanomedicine of human neuropeptide Y

“…This was in agreement with the results of another research group on NPY conformational changes with a model membrane system (dodecylphosphocholine micelle). This study revealed a raise in NPY α-helicity, particularly in its C-terminal segment upon interaction with the dodecylphosphocholine micelles 11. Given that the C-terminal of NPY is critical for binding to its targets, this conformational change favors peptide-receptor interaction 11, 20, 43, 44.…”

“…In addition, the peptide has been shown to modulate oxidative fuel selection6, bone homeostasis, intestinal fluid secretion, inflammatory responses and cancer growth 6–10. These responses are mediated, in part, through activation of NPY/ Y (1) receptor subtype in target organs and tissues 11–14. Overexpression of this receptor in malignant neoplasms was reported, particularly in breast cancer 10, 15.…”

Oligoclonal Antibody Targeting Ghrelin Increases Energy Expenditure and Reduces Food Intake in Fasted Mice

“…56, 57 Indeed, as is known for NPY and many other peptide-GPCR systems, amphiphilic stretches along the ligand hormone serve to first anchor the peptide onto the lipid bilayer and subsequently permit activation of the membrane bound receptor. 58, 59 Thus, perhaps the present oligoclonal approach more effectively prevented ultimate signaling at the GPCR, by also interfering with appropriate peptide “recognition”, rather than by relying only on immunoneutralization of “signaling” epitopes.…”

Unwinding of the C‐Terminal Residues of Neuropeptide Y is critical for Y2 Receptor Binding and Activation

“…As a consequence of the increasing angle between the NPY α-helix and the membrane surface, important membrane binding residues (L 17 /Y 20 /Y 21 ) [6] now become exposed to a rather polar environment, supported by the solution NMR data (Figure 2a). …”