TiPS- December 1991/Vol.

121

446
Headache2. 29-59
29 Kimball, R. W.. Friedman, A. P. and
V&Jo, E. (1960) Nwrof~y 10,107-111
30 Ogden, H. D. fl%3) Htadathr 3,29-31
31 Lance, J. W. (1973) Mecheabm end
Mnngmwnf of Headechr (2nd edn),
p. 121, Buttenvorths
32 Ostfeld, A. M. and Wolff, H. C. (1955)
Arch. Newel. Ps~yrhiaf.74, 131-136
33 Schoeffter, P. and Huyer, D. (19B9)
Nmvyt-Srhmitd.
Arch. Ph~nttacol. 340,

135-w
34 Humphrey, P. P. A. cf al. fl9BB) Br. J.
Pharmacol.94.11234132
35 Pemn,
M.
J., Feniuk, W. and
Humphrey, P. P. A. (1991) Br. 1. Phwmarol. 102,191-197
36 Sumner, M. and Humpixey, P. P. A.
(1989) Br. J. Pharmocal.98.29-31
37 Watts, A. D., Feniuk, W. and
Humphrey, P P. A. (1981) J. Phorm.
PhnrmPcol.33, SlS-520

Co-secretion of multiple signal molecules

from endocrine cells
via distinct exocytotic pathways

neurons and of many endocrine

cells, and led to the concept of the
APUD (amine-precursor uptake
and decarboxylation) neuroendocrine system6. The hypothesis that
all cells in this system share the
common embryological origin of
the neural crest has now been
disproven. Yet the special biochemical and functional similarity
of a variety of peptide-secreting
endocrine cells and of neurons has
been strengthened in recent years
and justifies the definition of
this class of endocrine cells as
neuroendocrine cells. Apart from
the contents and the membrane
proteins of large dense-core vesicles and secretory granulurs, both
neurons and neuroendocrine cells
express a number of ptokins that
are not expressed by other cells.
Furthermore, a variety of neuroendocrine cells have been shown
to express neuronal characteristics, including that of extending
neurite-like
ptocesses
when
grown under certain experimental
conditions. The best-characterized example of this phenotypic
shift is the nerve growth factorinduced neuronal differentiation
of chromaffin cells9. Similar
phenotypic shifts have been dernon&rated to occur spontaneously,
or after a variety of experimental
manipulations, in cells and cell
lines derived from other endocrine
tissues~*.

25
26
27

28

Effccrs(Saxena. I. R. and Fozard, J. R..

eds), pp. 42149, Birkh3user
Goadsby, P. J and Edvinsson,L. (1991)
CcphrluI$iIl11 (Suppl. 11). 3-l
Buzzi. M. C. and Moskuwitz. M. A.
(1990) Br. j. fhanr~acol.99, 202-206
Bucklev,T. L.. BrainS. D.. Ramport. M.
and Williams. T I. (1991) Br. 1. Pknr~tiecol. 103, 1515-1519
Anthony, M., Hinterberger, H. and
Lance, J. W. (1%9) R6. C/in. Sfsd.

Neurons secrete a cocktail of

neurotransmitter molecules via
both exocytotic and non-exocytotic mechanismslJ. Exocytotic
mechanisms involve at least two
pathways of secretion that use
either synaptic vesicles or large
dense-core vesicles as secretory
organelles (Fig. 1). Synaptic vesicles are a characteristic feature of
nerve endings and were considered until recently to be
neuron-specific organelles. They
contain only non-peptide neurotransmitters and play a dominant,
although not exclusive, role in the
fast, point-to-point
communication typical of the nervous system. Large dense-core vesicles
contain peptide neurotransmitters
and play an important role in
modulatory
signalling.
Large
dense-core vesicles may be seen
as the neuronal equivalent of secretory granules of endocrine cells,
which secrete peptide hormones.

Similarities behveen neurons and

peptide-secreting endocrine cells
The biogenesis and biochemical
properties of large dense-core
vesicles and secretory granules are
the same. Many of the same regulatory peptides that are secreted
by neurons via large dense-core
vesicles as neurotransmitters are
also secreted by endocrine cells
via secretory granules as peptide
hormones. In addition, a variety
of proteins thought to play a
general role in the organization of
secretory granules (the so-called
granins) are also present in large
dense-core
vesicles.
Amine
neurotransmitters are present in
secretory granules of certain
endocrine cells and, correspondingly, amines are present in the
large dense-core vesicles of certain
neuron2. In fact, the property to
uptake and decarboxylate amine
precursors has long been recognized as a special characteristic of

syluptic4ikeu&roveside8
Recent findings suggest the
existence of an additional general
similarity between neurons and
neuroendocrine cells. Following
the identification and characterization of several of the major
proteins of synaptic vesicle membranes, it has been found that
many of these proteins (e.g. synaptophysin, ~2% synaptotagmin,
synaptobrevin, SV2, rab3A) are
also expressed at significant
concenhations
by subsets of
neuroendocrine
cells. Within

TiPS- December1992[Vof. 121

neuroendocrine cells they are concentrated (and at least some of
them, e.g. synaptophysin and ~29,
are selectively localized) in the
membrane of a population of
microvesicles (synaptic-like microvesides) distinct from secretory
gran~les~*~*~(Figs 1 and 2). Like
authentic synaptic vesides, synaptic-like microvesides undergo
exocytosis, endocytosis and recyding17-9. One attractive possibility is that the function of
synaptic-like microvesides might
be to store and secrete neurotransmitters or similar molecules.
Recent studies carried out on g
cells of the pancreas have supported this hypothesis. For
many yea? it has been known
that the n euro&msmitter GABA,
as weU as the enzymes involved in
its synthesis (glutamic acid decarboxylase)
and
metabolism
(GABA transaminase), are expressed at high levels in g cells
of the islets of Langerhans (the
neuroendocrine ceUs that secrete
insuUn)a0.
Current
evidence
suggests that GABA is secreted
from g cells (which constitute the
core of the i&s) and acts as a
paracrine inhibitory signal molecule on oerl&e!ral islet cells
(pAmadly g&agon-secreting a
ceW? This view is consistent
wi& the direction of Mood flow in
islets (blood capillaries perfuse
first the g-cell core and then the
peripheral cells of the islets) and
with the antagonistic efkrts of
insulin endplllucagon on glucose
metabolism . Since GABA had
not been deteded in insulincontaining secretory granules, its
mechanism of secretion remained
undear.
The discovery of synaptic-like
microvesides raised the possibility that GABA secretion from fi
cells might be medfated by these
orgmelles. If synaptic-like microvesides of g cells are involved in
the storage of GABA, they should
share with synaptic vesides of
GABAergic neurons those properties that are related to GABA up
take and storage. Results obtained
so far using J3cells in situ and/or
J3-celllines have shown that this is
the case. First, the GABA synthesizing enzyme glutamic acid
decarboxylase, which in the terminals of GABAergic neurons is
concentrated
around
synaptic
vesides, was found to be concentrated around synaptic-like micro-

??

vesides of g ceils. Secondly,

regions of g cells enriched in
synaptic-like microvesicles were
also found to be enriched in
GABA immunoreactivity by immunofluorescence. Thirdly, a
GABA transport system driven by
a vacua&r proton pump, similer to
the system present in synaptic
vesicles, was present in synapticlike microvesicles of J3 cells
(A. Reetx, J. Hell, R. Jahn and
P. De CamiUi, unpublished).
There is no indication that
GABA might be present in synaptic-like microvesicles of neuroendocrine cells other than pancreatic Jl cells. However, results
obtained with microvesides of J3
cells support the possibility that
synaptic-like
microvesicles
of
neuroendocrine cells in general
may contain other mdecules
identical or similar to those
that are stored in synaptic vesides in neurons. Neurotransmitter phenotype varies from one
neuron to another. Therefore, a
similar heterogeneity of the neur(ltransmitter phenotype of endocrine cells would not be surprising. It will be of interest to
determine whether synaptic-like
microvesicles of chromafffn cells
and chromaffin cell-derived cell
lines contain acetylcholine, since
acetylcholine secretion from these
cells has been documentedas. Preliminary evidence obtained in undifferentiated PC12 cells suggests

that this is the case (T. Flatmark,

A. Regnier-Vigouroux and W.
Huttner, pers. commun.). So far
there is no positive evidence that
synaptic-like
microvesicles of
PC12 cells contain catecholiimines.
Growing evidence suggests a
widespread distribution of receptors for non-peptide neurotransmitters outside the nervous system. Nemotransmitters secreted
from neuroendocrine cells may
play a role as physiological effectors at such non-neuronel sites.
Synaplicvesidesarenot
mfic
Irrespective of whether synaptic-like microvesides of all neuroendocrine cells will turn out to
store neurotransmitter-like molecules and have a signalling function, synaptic vesicles can no
longer be considered a bona-fide
neuron-specific organelle. They
appear to represent a neuronspecific adaptation of synapticlike microvesicles. A transition
from synaptic-like microvesicles
to authentic synaptic vesides is
recapitulated when neuroendocrine cells undergo neuronaf differentiation. For example, neuronal differentiation of PC12 ceils
is accompanied by an increased
expression of the synapsins2, a
class of proteins selectMy associated with authentic synaptic vet+
ides in nerve terminals3. Clearly,
an important tine of research is

TiPS - December 1991/Vol. 121

448

the elucidaticn of the mOkCUlaf

mechanisms that CO&~!
the
switch from an endocrine to a
neuronal phenotype. Given their
many similarities to synaptic vesicles, synaptic-like microvesicles
are a useful model system to study
aspects of the cell biology of synaptic vesicles that cannot be easily
studied in nervous tissue or in
prima8y neuronal cultures. Several
endocrine cell lines are available
in which experiments of genetic
manipulation can be easily performed to study the role of specific
proteins in the exocytotidendocytotic cycling of synaptic vesicles
and synaptic-like microvesicles.
Some new insights into the cell
biology of synaptic vesicles have
already been obtained by the
study of synaptic-like microvesj&+5*7-19.

Do synaptic-like microvesicles of
all neuroendocrine cells indeed
contain neurotransmitter-like molecules? Is exocytosis of synapticlike microvesicles regulated? If
so, is exocytosis of synaptic-like
microvesicles and of secretory
granules differentially regulated?
These studies may open new directions in endocrine physiology
and pharmacology. In addition,
they may reveal previously unknown relationships
between
neuronal and endocrine diseases.
PIETRO

Drpartmrntof Cell Biology, Yale Uniucrsity

School of Medicine,333 Cedar Street, New
Huuor.CT 06S?O.USA.

References
1 Hiikfelt,

finding that synaptic vesicles are closely related to an

organelle that is present in neuroendocrine cellsraises the question
of whether the function of both
synaptic vesicles and synapticlike microvesicles is in turn somehow related to the functions of
organ&s
present in all cells.
Over the past several years it has
become clear that even the most
specialized cell characteristics represent adaptations of features expressed by all cells and can be
seen as the result of a process of
cellular evolution. It is intriguing
that many non-peptide neurotransmitters are metabolites in a
variety of metabolic pathways. It
is also intriguing that proteins
that transport metabolites across
membranes (glucose transporters)
are enriched in vesicular carriers,
which, like synaptic vesicles,
undergo
exocytotic/endocytotic
recycline. It is possible that early
in cellular evolution metabolic
pathways and signalling pathways were closely interrelated.
When the primary sequence of
synaptic vesicle neurotransmitter
carrier proteins is elucidated, it
will be of interest to search for
homologous proteins in microvesicles of non-neuronal, nonendocrine ceils.
The

Cl

cl

Many new and interesting

avenues of research in cellular
endocrinology are opening ahead.

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Etrata
5-HT advances 011hr fronts,
by AI&n Abbott (October 1991,
pp. 359-360)
The correct Ki value for
DALI6285at S-HT, receptors is
185nrbi,not 3nMas erroneously
published.
Ret toMforneump@idey:
mrrl$ pie subtypes and multiplc second 7
6Y
Martin C. Michcl (Octa et 1991,
pp. 389-394)
Figure 1 should not have been
cited on p. 390. Instead, the
final sentence of the left-hand
column on p. 391 should read
as below.

compound, i.e. C-terminal

fragments and analogues of
NPY (see Fig. l).
We apologize for these errors.

8 Cratzl, M. and La&q

K.. eds (1991)
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