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Neuropeptides and small-molecule amine transmitters: cooperative signaling in the nervous system

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Abstract

Neuropeptides are expressed in cell-specific patterns throughout mammalian brain. Neuropeptide gene expression has been useful for clustering neurons by phenotype, based on single-cell transcriptomics, and for defining specific functional circuits throughout the brain. How neuropeptides function as first messengers in inter-neuronal communication, in cooperation with classical small-molecule amine transmitters (SMATs) is a current topic of systems neurobiology. Questions include how neuropeptides and SMATs cooperate in neurotransmission at the molecular, cellular and circuit levels; whether neuropeptides and SMATs always co-exist in neurons; where neuropeptides and SMATs are stored in the neuron, released from the neuron and acting, and at which receptors, after release; and how neuropeptides affect ‘classical’ transmitter function, both directly upon co-release, and indirectly, via long-term regulation of gene transcription and neuronal plasticity. Here, we review an extensive body of data about the distribution of neuropeptides and their receptors, their actions after neuronal release, and their function based on pharmacological and genetic loss- and gain-of-function experiments, that addresses these questions, fundamental to understanding brain function, and development of neuropeptide-based, and potentially combinatorial peptide/SMAT-based, neurotherapeutics.

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Notes

  1. This number varies because neuropeptides can be counted as entities depending on individual molecular structure (PACAP-27 and PACAP-38 two distinct peptides) or by gene family (PACAP-27, PACAP-38, and PrP one entry). More important than an exact number is the fact that there are at least fifty separate neuropeptides with either known or putative physiological actions in the brain, paired with at least that number of cognate, although overlapping receptors, and that this is a lot more than the number of SMATs and SMAT receptors.

  2. The term ‘neurotransmission’ is used herein to refer to both fast transmission via ionotropic receptor activation, and slow transmission via metabotropic receptor activation, following SMAT or neuropeptide release from secretory vesicles upon neuronal excitation. We use the term SMATs, in this review, solely to provide a shorthand for referring to the small molecule amine-containing classical transmitters acetylcholine, dopamine, epinephrine, gamma-amino butyric acid, glutamate (GABA), histamine, norepinephrine, serotonin. These are referred to as ‘small’ due to their molecular weight (dopamine, 153; epinephrine, 183; GABA 103; glutamate 147; histamine 111; norepinephrine, 169; serotonin 176 g/mol) compared to neuropeptides (ranging from the smallest, the tripeptide TRH, 362 g/mol; to the relatively large, the 38-mer PACAP, 4534 g/mol).

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Acknowledgements

This work was supported by Grants UNAM-DGAPA-PAPIIT-IN216918, GI200121 & CONACYT-CB-238744 and CB-283279 to LZ, and NIMH-IRP-MH002386 to LEE. We acknowledge the anonymous reviewers of the manuscript for scrupulous attention to detail, and for several helpful suggestions. We thank our colleagues Scott Young and Chip Gerfen (NIMH) for perspectives and advice on nomenclature and concept development.

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Authors and Affiliations

  1. Section On Molecular Neuroscience, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, 49 Convent Drive, Room 5A38, Bethesda, MD, 20892, USA

    Lee E. Eiden & Sunny Z. Jiang

  2. Department of Physiology, School of Medicine, National Autonomous University of Mexico, Mexico City, Mexico

    Vito S. Hernández & Limei Zhang

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  1. Lee E. Eiden
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  2. Vito S. Hernández
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  3. Sunny Z. Jiang
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Eiden, L.E., Hernández, V.S., Jiang, S.Z. et al. Neuropeptides and small-molecule amine transmitters: cooperative signaling in the nervous system. Cell. Mol. Life Sci. 79, 492 (2022). https://doi.org/10.1007/s00018-022-04451-7

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