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KEY CONCEPTS

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  • Neuropeptides are small proteins or polypeptides that serve as neurotransmitters in the nervous system generally acting via G protein–coupled receptors. Other signaling peptides such as growth factors and cytokines are considered to be distinct even though they may have some overlapping functions.

  • Like the monoamines and acetylcholine, neuropeptide transmitters serve primarily modulatory roles in the nervous system.

  • The synthesis of neuropeptides, like that of all proteins, requires the transcription of DNA and translation of the resulting messenger RNA (mRNA) into protein.

  • Neuropeptides are synthesized as large precursor prepropeptides that undergo extensive posttranslational processing, which includes cleavages into smaller peptides and enzymatic modification. The “pre” refers to an N-terminal signal sequence that directs newly synthesized peptides into the regulated secretory pathway.

  • As a result of alternative RNA splicing and differential cleavage of propeptides in different tissues, a single gene can give rise to diverse signaling peptides with distinct functions.

  • Unlike small-molecule neurotransmitters, which are packaged in small synaptic vesicles, neuropeptides are generally packaged in large dense core vesicles; both types of vesicles may be found in the same neuron.

  • Neuropeptides may diffuse for long distances within the extracellular space before binding to their specific receptors.

  • Neuropeptide transmitters act almost exclusively via activation of G protein–coupled receptors.

  • Neuropeptides and their receptors modulate many diverse functions of the central nervous system, including sleep, arousal, reward, feeding, pain, cognition, stress responses, and emotions.

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INTRODUCTION

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Neuropeptides are short proteins or polypeptides that serve as neurotransmitters. They generally bind to G protein–linked receptors; there are rare exceptions in which peptides, such as insulin, have receptors that are enzymes (eg, protein tyrosine kinases) and act in a neurotransmitter-like fashion. Stimulation of G protein–coupled receptors produces slower responses than stimulation of ligand-gated channels (Chapter 4). Moreover, many of the actions mediated by G proteins and second messengers alter the response properties of neurons resulting in “modulation” rather than simple excitation or inhibition. More than 100 neuropeptide transmitters are known; they play diverse roles in the nervous system, including regulation of sleep and arousal, emotion, reward, feeding and energy balance, pain and analgesia, and learning and memory. However, much remains to be discovered about neuropeptide function because selective agonists and antagonists are still lacking for many neuropeptide receptors.

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This chapter focuses on general aspects of neuropeptide synthesis, release, and action, and describes several neuropeptides in more detail to illustrate these concepts. Several neuropeptides are discussed at greater length in other chapters; for example, hypothalamic peptides are considered in conjunction with the regulation of neuroendocrine function, stress responses, and feeding behavior (Chapter 10), and opioid peptides are considered in connection with pain (Chapter 11). Orexin (hypocretin) peptides are described in Chapter 6 because of their widely projecting organization in the nervous system and in Chapter 13 in relation to sleep and arousal.

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CHARACTERISTICS OF NEUROPEPTIDES

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Peptides are small proteins ...

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