Peptides in the Brain: Mass Spectrometry–Based Measurement Approaches and Challenges

Li, Lingjun; Sweedler, Jonathan V.

doi:10.1146/annurev.anchem.1.031207.113053

Cited by 131 publications

(173 citation statements)

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“…Neuropeptides and hormones comprise a diverse class of signaling molecules involved in numerous essential physiological processes, including analgesia, reward, food intake, learning and memory (1). Disorders of the neurosecretory and neuroendocrine systems influence many pathological processes.…”

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confidence: 99%

High-definition De Novo Sequencing of Crustacean Hyperglycemic Hormone (CHH)-family Neuropeptides

Jia

Hui

Cao

et al. 2012

Molecular & Cellular Proteomics

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A complete understanding of the biological functions of large signaling peptides (>4 kDa) requires comprehensive characterization of their amino acid sequences and posttranslational modifications, which presents significant analytical challenges. In the past decade, there has been great success with mass spectrometry-based de novo sequencing of small neuropeptides. However, these approaches are less applicable to larger neuropeptides because of the inefficient fragmentation of peptides larger than 4 kDa and their lower endogenous abundance. The conventional proteomics approach focuses on largescale determination of protein identities via database searching, lacking the ability for in-depth elucidation of individual amino acid residues. Here, we present a multifaceted MS approach for identification and characterization of large crustacean hyperglycemic hormone ( Neuropeptides and hormones comprise a diverse class of signaling molecules involved in numerous essential physiological processes, including analgesia, reward, food intake, learning and memory (1). Disorders of the neurosecretory and neuroendocrine systems influence many pathological processes. For example, obesity results from failure of energy homeostasis in association with endocrine alterations (2, 3). Previous work from our lab used crustaceans as model organisms found that multiple neuropeptides were implicated in control of food intake, including RFamides, tachykinin related peptides, RYamides, and pyrokinins (4 -6).Crustacean hyperglycemic hormone (CHH) 1 family neuropeptides play a central role in energy homeostasis of crustaceans (7-17). Hyperglycemic response of the CHHs was first reported after injection of crude eyestalk extract in crustaceans. Based on their preprohormone organization, the CHH family can be grouped into two sub-families: subfamily-I containing CHH, and subfamily-II containing molt-inhibiting hormone (MIH) and mandibular organ-inhibiting hormone (MOIH). The preprohormones of the subfamily-I have a CHH precursor related peptide (CPRP) that is cleaved off during processing; and preprohormones of the subfamily-II lack the CPRP (9). Uncovering their physiological functions will provide new insights into neuroendocrine regulation of energy homeostasis.Characterization of CHH-family neuropeptides is challenging. They are comprised of more than 70 amino acids and often contain multiple post-translational modifications (PTMs)

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confidence: 99%

High-definition De Novo Sequencing of Crustacean Hyperglycemic Hormone (CHH)-family Neuropeptides

Jia

Hui

Cao

et al. 2012

Molecular & Cellular Proteomics

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“…These cell-cell signaling peptides are produced from their corresponding precursor genes by cleavage at specific sites followed by additional posttranslational modifications, a complex process that can make bioactive peptides difficult to predict (2). The availability of genome sequences has led to a new, high-throughput approach for neuropeptide discovery: algorithms that predict cleavage sites in peptide precursors (3,4) followed by sequencing from brain samples with mass spectrometry (5)(6)(7).…”

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confidence: 99%

Quantitative peptidomics reveal brain peptide signatures of behavior

Brockmann

Annangudi²,

Richmond³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The honey bee genome predicts Ϸ100 peptides from 36 prohormones, but the functions of many of these peptides are unknown. We used differential isotope labeling combined with mass spectrometric analysis to quantify Ϸ50% of known bee brain peptides in the context of foraging, with 8 showing robust and dynamic regulation. Some showed differences in brain abundance as a function of experience; specifically, nectar and pollen collection led to quick changes in abundance. These changes were related to the act of food collection, not ingestion, because foragers bring food back to the hive for storage rather than eating it themselves. Other peptide differences in brain abundance were seen in bees that either flew to a nectar feeder or a pollen feeder, but did not yet collect any food. These differences likely reflect well-known predispositions of some bees to collect either nectar or pollen, but not both. Tachykinin, PBAN, and sNPF were among the peptides with the strongest changes in association with nectar and pollen foraging. These peptides are known to be involved in regulating food intake in solitary insects, suggesting an evolutionary connection between that behavior and social foraging. These results demonstrate that it is now possible to use quantitative peptidomics to help determine which brain peptides are bioactive and to elucidate their function in the regulation of behavior.Apis mellifera ͉ behavioral maturation ͉ foraging ͉ neuropeptides B rain peptides play an important role in orchestrating physiological and behavioral processes in animals by functioning as neurohormones, neuromodulators, and neurotransmitters (1). These cell-cell signaling peptides are produced from their corresponding precursor genes by cleavage at specific sites followed by additional posttranslational modifications, a complex process that can make bioactive peptides difficult to predict (2). The availability of genome sequences has led to a new, high-throughput approach for neuropeptide discovery: algorithms that predict cleavage sites in peptide precursors (3, 4) followed by sequencing from brain samples with mass spectrometry (5-7). Applying this methodology to the honey bee genome, Hummon et al. (6) predicted 36 peptide-encoding genes and confirmed 100 endogenous peptides in the bee brain, numbers similar to what is known for other animals such as the fruit fly (Drosophila melanogaster) and the house mouse (Mus musculus) (7,8).As with other species, however, the physiological and behavioral functions of most (neuro)peptides in the honey bee are unknown (2, 9-11). Until very recently, most brain peptides were discovered one at a time via biochemical techniques, and functional experiments focused on physiological effects (12). Recent advances in peptidomics have greatly accelerated peptide characterization (13-15). However, corresponding high-throughput approaches to discover peptide function have been much less common. A goal of this study was to determine whether combining a recently established quantitative peptidomic method with...

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“…Mass spectrometry, a rapid and sensitive method that has been used for the analysis of complex biological samples, can detect and identify the precise forms of neuropeptides without prior knowledge of peptide identity, with these approaches making up the field of peptidomics (7)(8)(9)(10)(11)(12). The direct tissue and single neuron analysis by MALDI MS has enabled the discovery of hundreds of neuropeptides in the last decade, and the neuronal homogenate analysis by fractionation and subsequent ESI or MALDI MS has yielded an equivalent number of new brain peptides (5).…”

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Endogenous Peptide Discovery of the Rat Circadian Clock

Lee

Atkins

Hatcher

et al. 2010

Molecular & Cellular Proteomics

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Understanding how a small brain region, the suprachiasmatic nucleus (SCN), can synchronize the body's circadian rhythms is an ongoing research area. This important time-keeping system requires a complex suite of peptide hormones and transmitters that remain incompletely characterized. Here, capillary liquid chromatography and FTMS have been coupled with tailored software for the analysis of endogenous peptides present in the SCN of the rat brain. After ex vivo processing of brain slices, peptide extraction, identification, and characterization from tandem FTMS data with <5-ppm mass accuracy produced a hyperconfident list of 102 endogenous peptides, including 33 previously unidentified peptides, and 12 peptides that were post-translationally modified with amidation, phosphorylation, pyroglutamylation, or acetylation. This characterization of endogenous peptides from the SCN will aid in understanding the molecular mechanisms that mediate rhythmic behaviors in mammals. Molecular & Cellular Proteomics 9:285-297, 2010.

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Peptides in the Brain: Mass Spectrometry–Based Measurement Approaches and Challenges

Cited by 131 publications

References 149 publications

High-definition De Novo Sequencing of Crustacean Hyperglycemic Hormone (CHH)-family Neuropeptides

High-definition De Novo Sequencing of Crustacean Hyperglycemic Hormone (CHH)-family Neuropeptides

Quantitative peptidomics reveal brain peptide signatures of behavior

Endogenous Peptide Discovery of the Rat Circadian Clock

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