ReviewNeuropeptides — an overview
Section snippets
Neuropeptides and their families
Peptides have been isolated from various organs; in particular, the porcine intestine and basal hypothalamus (see above) and, surprisingly, frog skin have been rich sources leading to the plethora of peptides now known. Ever since the mid 1970s a steady stream of peptides have been discovered and investigated, and in Table 1 mammalian peptides have been summarized. In fact, as indicated under the heading ‘Novel peptides’ in Table 1, the discovery period does not yet seem to be over. This is
Evolutionary aspects
Peptides occur in the whole animal kingdom (as well as in plants), including the hydra, a member of the coelenterates with a very simple nervous system. In this species numerous peptides, mainly belonging to the FMRF amide family, have been identified (see Grimmelikhuijzen et al., 1996). FMRF amide-like peptides are also expressed in ∼10% of the neurons in Caenorhabditis elegans, a nematode, and are encoded by at least 14 genes which are transcribed (Nelson et al., 1998). There are multiple
Peptide biosynthesis
The synthesis of neuropeptides is a complex process, distinctly different from that of classic transmitters (see Eipper and Mains, 1999). Virtually all bioactive neuropeptides are part of a larger, inactive molecule precursor which, after synthesis in the endoplasmic reticulum, is transferred to the Golgi apparatus for packaging, followed by centrifugal transport and exocytotic release. The precursor proteins are stored in the so called large dense core vesicles or secretory granules together
Peptide expression patterns
Peptides are expressed in neurons in at least three types of mode (Table 2) (see also Tohyama, 1992). Thus, some peptides are present at high levels under normal circumstances, which indicates that they are functionally available at any time. A second type are peptides normally expressed at low or undetectable levels. They are then upregulated under certain conditions, for example after nerve injury (see below). Thus a specific stimulus is required for such a peptide to become functionally
Distribution and coexistence of messengers
Peptides are present in all parts of the nervous system — the brain, spinal cord, gastrointestinal tract, autonomic and sensory ganglia. However, each peptide has its unique distribution pattern as exemplified in Fig. 2, showing four peptides in the mouse dorsal hippocampus, galanin [Fig. 2(a)], NPY [Fig. 2(b)], CCK [Fig. 2(c)] and enkephalin [Fig. 2(d)]. Initially, it was assumed that these ‘peptidergic’ systems were different from and complementary to previously transmitter-characterized
Plasticity in peptide expression
There is evidence that peptide levels may vary considerably during different conditions, including endogenous diurnal variations and after experimental manipulations. Since replacement after release almost exclusively seems to occur via new synthesis in cell bodies, neuronal activation and peptide release from nerve endings are followed by a rapid upregulation of mRNA levels (see, for example, Schalling et al., 1987). Thus, there is a considerable delay until peptide levels in the nerve endings
Neuropeptides and drug development
There are at least three types of ‘peptide’ drugs, antagonists, agonists and peptidase inhibitors, the latter preventing peptide breakdown and thus strengthening the peptidergic transmission (agonist effect). The early antagonists were of peptidergic nature, mostly D-substituted analogs, one of the first being [D-Pro2, D-Phe7, D-Trp9] substance P (Folkers et al., 1982), a substance P antagonist. A non-peptide substance P antagonist was then developed ten years later (Snider et al., 1991).
General aspects
In spite of studies demonstrating interesting actions of peptides when exogenously applied, and in spite of the wealth of peptides and all efforts invested in peptide research, including studies with antagonists, it has been difficult to define an exact role for many of these molecules in nervous system function. There are of course, several peptides for which an unequivocal physiological function has been defined, such as the posterior pituitary hormones (oxytocin, vasopressin) originating in
Neuropeptides in glia
There is evidence that neuropeptides, in spite of their ‘name’ (!), are also expressed in glial cells. Most studies focus on expression in cell cultures, including demonstration of pre-proenkephalin mRNA, preprosomatostatin mRNA and enkephalin peptides in astrocytes (Klein and Fricker, 1992, Melner et al., 1990, Schwartz and Simantov, 1988, Shinoda et al., 1992, Shinoda et al., 1989, Spruce et al., 1990, Steine-Martin et al., 1991, Vilijn et al., 1988). However, atrial natriuretic peptide has
Trophic effects of peptides
Increasing evidence indicates that peptides exert trophic actions and have roles during the embryonic period (see Schwartz, 1990, Strand et al., 1991). It was initially noticed that several peptides, for example somatostatin, can only be seen during the embryonic period in certain systems and then disappear, suggesting a developmental role (see Tohyama, 1992). Some early results are listed in Table 5. To mention a few recent studies, VIP has been shown to have a dramatic effect on growth of
Clinical studies
In the beginning of the peptide era it was predicted that peptides are involved in disease, and that consequently drugs interfering with peptidergic mechanisms could have therapeutic effects. For example, the realization that substance P is present in small diameter fibers of presumptive nociceptive sensory neurons, and the discovery of endogenous ligands for the opiate receptors suggested a rapid progress in understanding and treatment of various pain states. To date this prediction has not
Conclusion
Major progress has been made in the field of neuropeptides. Peptide receptors have been identified, drugs have been developed and novel insights into the regulation of peptide synthesis have been obtained. Still, the physiological roles of neuropeptides often remain elusive, and both transmitter-like functions, modulation and trophic actions have to be considered. There is evidence that peptides may exert their main actions when the nervous system is ‘stressed’, challenged or afflicted by
Acknowledgements
These studies were supported by Marianne and Marcus Wallenberg's Foundation, Knut and Alice Wallenberg's Foundation, a Bristol-Myers Squibb Unrestricted Neuroscience Grant and the Swedish MRC (04X-2807).
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