Understanding Neuropeptide Transmission in the Brain by Optical Uncaging and Release

Abstract

Neuropeptides are abundant and essential signaling molecules in the nervous system involved in modulating neural circuits and behavior. Neuropeptides are generally released extrasynaptically and signal via volume transmission through G-protein-coupled receptors (GPCR). Although substantive functional roles of neuropeptides have been discovered, many questions on neuropeptide transmission remain poorly understood, including the local diffusion and transmission properties in the brain extracellular space. To address this challenge, intensive efforts are required to develop advanced tools for releasing and detecting neuropeptides with high spatiotemporal resolution. Because of the rapid development of biosensors and materials science, emerging tools are beginning to provide a better understanding of neuropeptide transmission. In this perspective, we summarize the fundamental advances in understanding neuropeptide transmission over the past decade, highlight the tools for releasing neuropeptides with high spatiotemporal solution in the brain, and discuss open questions and future directions in the field.

Keywords: Brain; Light; Neuropeptide release; Neuropeptide sensor; Neuropeptide transmission.

Figure 1.

(A) Chemical structures change of caged-peptides after UV light irradiation. CYLE: carboxynitrobenzyl modified [Leu]-enkephalin; N-MNVOC-LE N-(α-methyl-6-nitroveratryloxycarbonyl) modified [Leu]-enkephalin. The caging groups are indicated in red. (B) Schematic of preparation of somatostatin-encapsulated photosensitive nanovesicles (Au-nV-SST) and photorelease by the near-infrared laser pulses. The illustration of Au-nV-SST was adapted with permission from Ref [7].

Figure 2.

Integrating neuropeptide release and sensing to probe neuropeptide transmission. (A) Schematic of cell-based neurotransmitter fluorescent engineered reporter (CNiFERs) for neuropeptide detection. (B) Schematic of genetically encoded GPCR-based sensors for neuropeptide detection.

Figure 3.

The diverse physicochemical properties of neuropeptides. (A) Pair plot comparing the molecular weight (kDa), theoretical net charge at a physiologic pH of 7.4, and the Potential Protein Interaction Index (PPI-Index), a predictor of a polypeptide’s propensity to bind other proteins/receptors, for all 283 human neuropeptides in the NeuroPep database. The properties were estimated from the peptide sequences using the peptides.py package (https://github.com/althonos/peptides.py). Note that the diagonal edge of the pair plot shows the distributions of each property. (B) A selection of human neuropeptide structures collected from the RCSB Protein Data Bank and AlphaFold Protein Structure Database^, highlighting the diversity of neuropeptide structure and physicochemical properties, including the 38 amino acid variant (blue) of pituitary adenylate cyclase-activating peptide (PACAP), Neuropeptide Y (red), glucagon (green), the 27 amino acid variant of PACAP (orange), Somatostatin 14 (light blue), and Dynorphin A (1-13) (yellow). The neuropeptide structures were rendered using the Visual Molecular Dynamics (VMD) software.