Neuropeptides

Neuropeptides are the largest and most diverse class of signalling molecules in the brain. Neuropeptides act as neurotransmitters, as modulators of neurotransmission by other neurotransmitters, as autocrine/paracrine regulators, and as hormones. Some of the chemokines are also neuropeptides.

Classic neuropeptides are formed by enzymatic processing of gene-encoded precursor molecules. Precursors are produced mainly in neurons. Neuropeptides can be classified into families based on the genes that encode the precursor peptides. Human genome contains ∼90 genes that encode neuropeptide precursors. Many classical neuropeptides are synthesized not only in neurons but also in endocrine glands, functioning as peptide hormones. Strict definition of neuropeptides excludes peptide hormones that are not synthesized by neurons although they signal to the brain; these include insulin and leptin.

Neuropeptides, like other hormones and neurotransmitters, are stored and, by demand, secreted via regulated secretory pathways, and bind to specific G-protein coupled or metabotropic receptors on target cells. These receptors can be targeted with specific radioligands for PET imaging. Neuropeptides modulate the signalling of other neurons, but they can directly innervate non-neurons via synaptic contact in peripheral organs (Salio et al., 2006; Burbach, 2010; Merighi et al., 2011; Elphick et al., 2018).

Neuropeptide gene families the functional peptides that they encode include:

Opioid gene family

• Pro-enkephalin gene (PENK): Leu- and Met-enkephalin, amidorphin, adrenorphin
• Pro-opiomelanocortin gene (POMC): melanocyte-stimulating hormones, adrenocorticotropic hormone (ACTH), α- β- and γ-endorphins
• Pro-dynorphin gene (PDYN): dynorphin A and B
• pre-pronociceptin gene (PNOC): nociceptin, neuropeptide 1 and 2

Vasopressin/oxytocin gene family

• Vasopressin gene (AVP): vasopressin, neurophysin II
• Oxytocin gene (OXT): oxytocin, neurophysin I

CCK/gastrin gene family

• Gastrin gene (GAST): gastrin
• Cholecystokinin gene (CCK): cholecystokinin (CCK)

Somatostatin gene family

• Somatostatin gene (SST): somatostatin
• Cortistatin gene (CST): cortistatin

F- and Y-amide gene family

• Neuropeptide FF gene (NPFF): neuropeptides FF, AF, and SF
• Neuropeptide Y gene (NPY): neuropeptide Y (NPY)
• Pancreatic polypeptide gene (PPY): PPY
• Peptide YY gene (PYY): peptide YY

Calcitocin gene family

• Calcitonin I gene (CALCA): calcitonin
• Calcitonin II gene (CALCB): calcitonin gene related peptides 1 and 2 (α-CGRP, β-CGRP)
• Islet amyloid polypeptide gene (IAPP): IAPP (amylin)
• Adrenomedullin gene (ADM): adrenomedullin
• Adrenomedullin-2 gene (ADM2): adrenomedullin-2

Natriuretic factor gene family

• Atrial natriuretic factor gene (NPPA): atrial natriuretic factor (ANF)
• Brain natriuretic factor gene (NPPB): brain natriuretic factor (BNF)
• Natriuretic peptide precursor C gene (NPPC): C-type natriuretic peptide (CNP)

Bombesin-like peptide gene family

• Gastrin-releasing peptide gene (GRP): GRP
• Neuromedin B gene (NMB): neuromedin B

Endothelin gene family

• Endothelin 1 gene (EDN1): endothelin 1 (ET-1)
• Endothelin 2 gene (EDN2): endothelin 2 (ET-2)
• Endothelin 3 gene (EDN3): endothelin 3 (ET-3)

Glucagon/secretin gene family

• Glucagon gene (CGC): glucagon, glucagon-like peptides GLP-1 and GLP-2, glicentin
• Secretin gene (SCT): secretin
• Vasoactive intestinal peptide gene (VIP): VIP
• Growth hormone releasing hormone gene (GHRH): GHRH
• Gastric inhibitory peptide gene (GIP): GIP

CHR-related gene family

• Corticotropin-releasing hormone gene (CRH): CRH
• Urocortin gene (UCN): Urocortins

Kinin and tensin gene family

• Preprotachykinin A gene (TAC1): substance P, neurokinin A, neuropeptide K, neuropeptide γ
• Preprotachykinin B gene (TAC3): neuromedin K, neurokinin B
• Kininogen-1 gene (KNG1): bradykinin, kallidin
• Angiotensin gene (AGT): angiotensin I and II
• Neurotensin gene (NTS): neurotensin, neuromedin N

Motilin family

• Motilin gene (MLN): motilin
• Ghrelin gene (GHRL): ghrelin, obestatin

Insulin family

• Insulin gene (INS): insulin
• IGF-1 gene (IGF1): IGF-1
• IGF-2 gene (IGF2): IGF-2
• Relaxin-1 gene (RLN1): relaxin-1
• Relaxin-2 gene (RLN2): relaxin-2
• Relaxin-3 gene (RLN3): relaxin-3

Adipose neuropeptides

• Leptin/ob gene (LEP): leptin
• Adiponectin gene (ADIPOQ): adiponectin
• Visfatin gene (PBEF1): visfatin-1
• Resistin gene (RETN): resistin

No-family neuropeptides

• Thyrotropin-releasing hormone gene (TRH): TRH
• Parathyroid hormone-like hormone gene (PTHLH): osteostatin
• Cocaine- and amphetamine-regulated transcript gene (CART): CART
• Prolactin gene (PRL): prolactin
• Apelin gene (APLN): apelins
• Metastasis suppressor gene (KISS1): metastin, kisspeptins

PET imaging

Several radiolabelled peptides have been developed targeting neuropeptide systems, for example somatostatin receptors, GLP-1 receptor, and natriuretic peptide receptor C.

See also:

• Peptides
• Oligonucleotides
• Immuno-PET
• Nanoparticles

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Literature

Fonseca ICF, Castelo-Branco M, Cavadas C, Abrunhosa AJ. PET imaging of the neuropeptide Y system: a systematic review. Molecules 2022; 27, 3726. doi: 10.3390/molecules27123726.

Jackson IM, Scott PJH, Thompson S. Clinical applications of radiolabeled peptides for PET. Semin Nucl Med. 2017; 47(5): 493-523. doi: 10.1053/j.semnuclmed.2017.05.007.

Kastin AJ (ed.): Handbook of Biologically Active Peptides, 2nd ed., Academic Press, 2013. eISBN: 9780123850966.

Merighi A (ed.): Neuropeptides - Methods and Protocols. Springer, 2011. doi: 10.1007/978-1-61779-310-3.

Roivainen A, Jalkanen S, Nanni C. Gallium-labelled peptides for imaging of inflammation. Eur J Nucl Med Mol Imaging 2012; 39(Suppl 1): S68-S77. doi: 10.1007/s00259-011-1987-6.

Tags: Peptides, Neuropeptides, Cytokines

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Updated at: 2023-01-16
Created at: 2017-10-28
Written by: Vesa Oikonen