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The Journal of Neuroscience, January 1, 1999, 19(1):206-219
Pituitary Adenylate Cyclase-Activating Polypeptide and Melatonin
in the Suprachiasmatic Nucleus: Effects on the Calcium Signal
Transduction Cascade
Michael D. A.
Kopp1, 2,
Christof
Schomerus1,
Faramarz
Dehghani1,
Horst-Werner
Korf1, and
Hilmar
Meissl2
1 Dr. Senckenbergische Anatomie, Anatomisches
Institut II, Johann Wolfgang Goethe-Universität, D-60590
Frankfurt, Germany, and 2 Max-Planck-Institut für
Physiologische und Klinische Forschung, W. G. Kerckhoff-Institut, D-61231 Bad Nauheim, Germany
The suprachiasmatic nucleus (SCN) harbors an endogenous oscillator
generating circadian rhythms that are synchronized to the external
light/dark cycle by photic information transmitted via the
retinohypothalamic tract (RHT). The RHT has recently been shown to
contain pituitary adenylate cyclase-activating polypeptide (PACAP) as
neurotransmitter/neuromodulator. PACAPergic effects on
cAMP-mediated signaling events in the SCN are restricted to distinct
time windows and sensitive to melatonin. In neurons isolated from the
SCN of neonatal rats we investigated by means of the fura-2 technique
whether PACAP and melatonin also influence the intracellular calcium
concentration ([Ca2+]i). PACAP
elicited increases of [Ca2+]i in 27%
of the analyzed neurons, many of which were also responsive to the RHT
neurotransmitters glutamate and/or substance P. PACAP-induced changes
of [Ca2+]i were independent of cAMP,
because they were not mimicked by forskolin or 8-bromo-cAMP. PACAP
caused G-protein- and phospholipase C-mediated calcium release from
inositol-trisphosphate-sensitive stores and subsequent protein kinase
C-mediated calcium influx, demonstrated by treatment with GDP- -S,
neomycin, U-73122, calcium-free saline, thapsigargin,
bisindolylmaleimide, and chelerythrine. The calcium influx was
insensitive to antagonists of voltage-gated calcium channels of the L-,
N-, P-, Q- and T-type (diltiazem, nifedipine, verapamil,  -conotoxin,
-agatoxin, amiloride). Immunocytochemical characterization of the
analyzed cells revealed that >50% of the PACAP-sensitive neurons were
GABA-immunopositive. Our data demonstrate that in the SCN PACAP affects
the [Ca2+]i, suggesting that
different signaling pathways (calcium as well as cAMP) are involved in
PACAPergic neurotransmission or neuromodulation. Melatonin did not
interfere with calcium signaling, indicating that in SCN neurons the
hormone primarily affects the cAMP signaling pathway.
Key words:
PACAP; substance P; glutamate; retinohypothalamic tract; suprachiasmatic nucleus; melatonin; circadian rhythm; calcium; phospholipase C; protein kinase C; GABA
Copyright © 1999 Society for Neuroscience 0270-6474/99/191206-14$05.00/0
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