into the single unified field of neuroendocrinology. Neuropeptides can mediate
communication between neurons, either directly or indirectly. Thus neurons are capable
of synthesizing peptides and using them for communication either over a short range
(synaptically, i.e., neural) or over a long range (via the circulation, i.e., endocrine); con-
versely, endocrine glands produce compounds that can act as neurotransmitters as well
as hormones. About 100 neuropeptides have been described, and the end is not in sight.
Neuropeptides share a number of functional characteristics with small amine neuro-
transmitters: their release is normally Ca^2 +dependent, and they operate through ion
channels or second messengers. There are, however, a number of complicating factors
peculiar to this all-important group of messengers.
We have already discussed the co-occurrence of small amine and peptide neuro-
transmitters: their release is normally Ca^2 +dependent, and they operate through signal
transmission. They are also capable of regulating each other’s release and even the syn-
thesis, clustering, and affinity of receptors. Neuroendocrine cells are capable of pro-
ducing more than one peptide, and thus an amine–peptide as well as a peptide–peptide
combination is possible. It is known, for instance, that the vagus nerve contains
substance P, vasointestinal peptide, enkephalin, cholecystokinin, and somatostatin—
peptides with a hybrid combination of neural and hormonal communication properties.
Our ideas about the selectivity of peptide neurohormones have also undergone pro-
found development. Since most of these neurohormones act both centrally and periph-
erally, one has to surmise that the receptors in different organs are isoreceptors,in the
sense of, say, the β 1 - and β 2 -adrenoceptors. Although the neuropeptide binds to both,
the “command” executed will be appropriate to the receptor and the organ. In addition,
different parts of the peptide may carry a different message, as in the peripheral pain
mediation of substance P by the C-terminus and the central analgesia by the N-terminus.
This hierarchy of selectivities is necessary in a neurohormone that is distributed by the
blood circulation because all cells are equally exposed to its message. There is also a
difference in the onset and duration of action between the ultrafast, small amine neuro-
transmitters and the slow but durable and persistent peptides. It seems that the two
classes also differ in the average amount present in tissue (1–10 μmol/mg tissue for
amines; fmol to pmol/mg tissue for peptides); this difference, however, need not involve
the rate of turnover. Peptide concentrations can also vary by several orders of magni-
tude in different organs.
The metabolism of neuropeptides is not noticeably different from that of other
proteins. Neuropeptides are unusual, however, in that the majority are synthesized in
the form of prohormonesthat may contain several copies of smaller individual peptides,
sometimes even of unrelated activity. These have to be modified (e.g., by glycosylation,
disulfide bridge formation, methylation, etc.), cleaved by exo- and endopeptidases, and
the fragments further modified (e.g., by C-terminal amidation, pyroglutamate forma-
tion). These processes vary from organ to organ; thus the same prohormone can undergo
alternative post-translational modification, appropriate to the specific needs of the organ
or species. Neuropeptides do not undergo reuptake like the majority of amine transmit-
ters, but rather are eliminated by proteolysis. Protein synthesis must occur in the cell
body of the neuron, and the protein must be packaged in the Golgi apparatus and trans-
ported by a fast transport system (3–5 μm/sec) to the synapse; thus we need to learn more
about neuropeptide economies in terms of production and use.It is obvious that the com-
plex nature of the neuropeptide and the variety of factors involved in neuroendocrine
HORMONES AND THEIR RECEPTORS 339