Kaplan + Sadock's Synopsis of Psychiatry, 11e

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1.4 Neurophysiology and Neurochemistry

Figure 1.4-11 Schematics illustrating the gene structure, preprohormone messenger RNA (mRNA), and processed neuropeptides of thyrotropin-releasing hormone (TRH), corticotropin-releasing factor (CRF), oxytocin (OT), arginine vasopressin (AVP), and neurotensin (NT). Boxed regions indi- cate the locations of the exons in the respective genes. Shaded or hatched regions indicate coding regions. Each preprohormone begins with a signal peptide (SP) sequence. Black boxes indicate the locations of the sequences encoding the neuropeptide. (From Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9 th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:87.)

Molecular technology has made it possible to clone and characterize neuropeptide receptor genes and complementary DNAs (cDNAs). This is most often accomplished in one of three ways. First, the neuropep- tide receptor protein is biochemically purified and partially sequenced, which allows the development of oligonucleotide probes that can be used to isolate the cDNA encoding the protein from a cDNA library. A second approach involves producing expression libraries in which cells containing the receptor cDNA can be isolated based on their ability to bind to a radiolabeled peptide ligand. Finally, many neuro- peptide receptors are now isolated based on their sequence homology with other known peptide receptors. Once the cDNA of the receptor has been isolated, it can be used to produce purified receptor protein for

structural and functional studies. By mutation of specific amino acids in the receptor structure and determination of relative binding affinities of peptides with various amino acid substitutions, it is possible to elucidate the nature of the ligand–receptor interaction. This information facili- tates the development of drugs that specifically modulate receptor func- tion, including nonpeptide drugs, leading to the ability to manipulate peptide systems in ways that are currently enjoyed by the more classic neurotransmitters. The availability of cDNAs encoding the receptor also permits the neuroanatomical mapping of the receptor-producing cells in the brain, which is critical for understanding the neural circuits modu- lated by the peptide. Finally, with the cloned receptor in hand, it is pos- sible to use transgenic techniques, such as targeted gene overexpression