Shuttling of Peptide-Drug Conjugates by G Protein-Coupled Receptors Is Significantly Improved by Pulsed Application.

G protein-coupled receptors (GPCRs) can be used to shuttle peptide-drug conjugates into cells. But, for efficient therapy, a high concentration of cargo needs to be delivered. To explore this, we studied the pharmacologically interesting neuropeptide Y receptor (Y R) in one recombinant and three oncogenic cell systems that endogenously express the receptor.

Unusually persistent Gα-signaling of the neuropeptide Y receptor depletes cellular G pools and leads to a G-refractory state.

Background: A sensitive balance between receptor activation and desensitization is crucial for cellular homeostasis. Like many other GPCR, the human neuropeptide Y receptor (hYR) undergoes ligand dependent activation and internalization into intracellular compartments, followed by recycling to the plasma membrane. This receptor is involved in the pathophysiology of distinct diseases e.

Biased agonists at the human Y receptor lead to prolonged membrane residency and extended receptor G protein interaction.

Functionally selective ligands to address specific cellular responses downstream of G protein-coupled receptors (GPCR) open up new possibilities for therapeutics. We designed and characterized novel subtype- and pathway-selective ligands. Substitution of position Q of neuropeptide Y to glycine (G-NPY) results in unprecedented selectivity over all other YR subtypes.