Proteomics and Beyond

Shotgun proteomics takes its name from shotgun DNA sequencing, in which long DNA sequences are disassembled into shorter, easily readable components and reassembled. Shotgun proteomics works in much the same way as the proteome of a cell is digested, subjected to analysis on mass spectrometry, and "reassembled" into proteins identified through a sophisticated bioinformatic analysis of the protein "fingerprint." At first glance, such an approach might seem problematic, as a tripeptide would have the same mass regardless of the order of the amino acids; however, ionization of the peptide reveals the order of the amino acids. It is the computational algorithms that allow this identification. A recent review explains this in language that any biologist (or psychiatrist) can understand (Marcotte 2007).

Analysis of the proteome has the potential to yield much more information than simply the identity of the proteins being expressed in a given cell at a given time. Drugs that mimic, antagonize, or alter metabolism of neurotransmitters and neuromodulators comprise the vast majority of the current psychiatric armamentarium. These drugs, often used chronically, have been shown to have long-term effects, altering second-messenger systems. These second messengers (e.g., cAMP, inositol-1,4,5-triphosphate [IP3], cyclic guanosine monophosphate [cGMP]) activate or inhibit enzymes that modify proteins covalently. Phosphorylation, prenylation, and glycosylation are examples of these modifications, all of which can be determined in mass spectroscopic proteomic analysis.

In addition to—and, in part, due to—the modifications discussed above, molecules involved in neurotransmitter response and responsiveness move among cellular compartments in response to neurotransmitters, neuromodulators, and drugs that affect these. A simple example might be the agonist-induced depalmitoylation of the ft subunit of the stimulatory G protein (Gsi:;) that results in its translocation from the plasma membrane (Wedegaertner and Bourne 1994; Yu and Rasenick 2002). We have demonstrated that this translocation is due to collection of G proteins in lipid rafts structures that either amplify or attenuate signaling (Allen et al. 2005, 2007). A catalog of these protein shifts during disease or response to drug can be easily assembled.

As noted above, G protein-coupled receptors comprise targets for a major component of drugs used in psychiatry. Curiously, many of these drugs were thought to have a single site of action until a screening/informatics approach was applied to them. Receptoromics allows screening of compounds for their agonist or antagonist effects on receptors measured through batteries of cells selectively expressing a single species of G protein-coupled receptor (or other receptor or transporter). Results from these studies have been both informative and surprising (Strachan et al. 2006). For example, atypical antipsychotics have been selected for their antagonist properties at the 5-HT2A receptor. Some of these drugs, such as olanzapine, have been associated with excessive weight gain, and this appears to be due to interaction with H1 receptors—not related to the therapeutic profile of the drug. Other effective antipsychotic drugs may owe their efficacy to actions at a panel of receptors that, when combined, contribute to a therapeutic whole. The ability to screen libraries of compounds against a large number of receptor targets makes design and identification of new drugs an exciting possibility.

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