The processing of neuropeptide precursors, which takes place within the endoplasmic reticulum, Golgi apparatus, and transporting vesicles, makes it possible for neurons to synthesize a large number of endogenous opioids from just three different pe ptide chains. Such post-translational processing also makes it possible for cells to efficiently react to changing environmental conditions. Because much of the post-translational processing is regulated by feedback mechanisms, the concentration of a pa rticular neurotransmitter can be altered simply, by splicing one of the three precursor peptides at different signal sites instead of altering the level of mRNA that is constructed during transcription in the nucleus.
Gene transcription in the nucleus results in a newly formed protein-coding strand of mRNA. This mRNA molecule travels to the cytoplasm, where translation begins on a free-floating ribosome. In the case of neuropeptides, translation starts with th e construction of a "signal sequence" at the N-terminus of the peptide. This short sequence of hydrophobic amino acids directs the mRNA, the attached ribosome, and the "nascent" peptide chain to the membrane of the endoplasmic reticulum (ER).
The translational complex binds to the endoplasmic reticulum (ER) membrane, translation continues, and the growing chain of polypeptides is "fed" into the lumen of the ER. When transcription is complete, the result is a string of amino acids contained completely within the ER lumen and anchored to the membrane by the signal sequence.
Processing of the pre-propeptide in the endoplasmic reticulum (ER) begins with the cleavage of the signal sequence by an enzyme called a signal peptidase. Peptidases are enzymes which cleave designated sections of a propeptide by hydrolyzing the peptide bonds that hold amino acids together. Specific sequences along the chain of amino acids serve as signals to direct the enzymes where to cleave. The ER contains numerous peptidases, each type recognizing different signals and cleaving at different locations, resulting in the specificity necessary to synthesize the wide range of neurotransmitters that may be derived from just one propeptide (in this case, the synthesis of one of several possible endogenous opioids from one of three precursor peptides). Which enzymes are present in a particular neuron dictates which neuropeptides will be synthesized and ultimately depends upon the genes that are expressed by the cell, the changing demands of the cell, and which area of the brain the cell is located in.
After processing in the Endoplasmic Reticulum (ER), a sequence of amino acids on the propeptide directs the molecule to the Golgi apparatus, where it is further processed by peptidases, packaged into a vesicle along with a pool of peptidases, and released for transport down the axon.