Why are neuropeptides released only when a neuron fires hard? · Grey Matter

Peptides are stored in large dense-core vesicles that sit away from the active zone, outside the tight calcium clouds around the release-site channels.

Why are neuropeptides released only when a neuron fires hard?

Peptides are stored in large dense-core vesicles that sit away from the active zone, outside the tight calcium clouds around the release-site channels. A single spike raises calcium enough to fuse the small vesicles docked next to the channels but not these distant ones; high-frequency firing or bursts let calcium build up throughout the terminal, and only then do dense-core vesicles fuse, often outside the synapse. Since peptides are made in the cell body and shipped down the axon, their supply at the terminal is also limited. The result is a two-level code: the small transmitter reports every spike, the peptide reports sustained, intense activity.