Sorting of neuropeptides and neuropeptide receptors into secretory pathways

There are two major secretory pathways in neurons, the regulated pathway and the constitutive pathway. Neuropeptides and other regulated secretory proteins are known to be sorted into large dense-core vesicles of the regulated pathway in the trans-Golgi network and are secreted upon stimulus-induced increases in intracellular Ca(2+). The newly synthesized cell surface receptors are usually sorted into microvesicles of the constitutive pathway and inserted into the plasma membrane by spontaneous exocytosis. Small-diameter sensory neurons in dorsal root ganglia and pheochromocytoma cells express neuropeptides (e.g., substance P) and several neuropeptide receptors including opioid receptors. The mu-opioid receptors are delivered to the cell surface through the constitutive pathway, whereas another type of opioid receptor, the delta-opioid receptor, is often found in the membrane of large dense-core vesicles and can be inserted into the plasma membrane when exocytosis occurs. Recent studies show that sequences with opposite electrical polarity within the prohormones of substance P are essential for their sorting into large dense-core vesicles. Moreover, the delta-opioid receptor is sorted into large dense-core vesicles by its interaction with protachykinin, a prohormone of substance P. These findings provide insight into the molecular mechanisms that determine the sorting and trafficking of neuropeptides and neuropeptide receptors in neurons.