Abstract

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 μ-opioid receptors are delivered to the cell surface through the constitutive pathway, whereas another type of opioid receptor, the δ-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 δ-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.

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