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The Journal of Neurophysiology Vol. 87 No. 5 May 2002, pp. 2490-2504
Copyright ©2002 by the American Physiological Society
/IP3/Calcineurin Signaling Cascade
1Department of Physiology/Northwestern University Institute for Neuroscience, Northwestern University Medical School, Chicago, Illinois 60611; and 2Institut für Biochemische Pharmakologie, A-6020 Innsbruck, Austria
Day, Michelle,
Patricia A. Olson,
Josef Platzer,
Joerg Striessnig, and
D. James Surmeier.
Stimulation of 5-HT2 Receptors in Prefrontal
Pyramidal Neurons Inhibits Cav1.2 L-Type Ca2+
Currents Via a PLC/IP3/Calcineurin Signaling Cascade. J. Neurophysiol. 87: 2490-2504, 2002. There is growing evidence linking
alterations in serotonergic signaling in the prefrontal cortex to the
etiology of schizophrenia. Prefrontal pyramidal neurons are richly
innervated by serotonergic fibers and express high levels of
serotonergic 5-HT2-class receptors. It is
unclear, however, how activation of these receptors modulates cellular
activity. To help fill this gap, whole cell voltage-clamp and
single-cell RT-PCR studies of acutely isolated layer V-VI prefrontal
pyramidal neurons were undertaken. The vast majority (>80%) of these
neurons had detectable levels of 5-HT2A or
5-HT2C receptor mRNA. Bath application of
5-HT2 agonists inhibited voltage-dependent Ca2+ channel currents. L-type
Ca2+ channels were a particularly prominent
target of this signaling pathway. The L-type channel modulation was
blocked by disruption of G
q signaling or by
inhibition of phospholipase C
. Antagonism of intracellular inositol
trisphosphate signaling, chelation of intracellular
Ca2+, or depletion of intracellular
Ca2+ stores also blocked this modulation.
Inhibition of the Ca2+-dependent phosphatase
calcineurin prevented receptor-mediated modulation of L-type currents.
Last, the 5-HT2 receptor modulation was robustly
expressed in neurons from Cav1.3 knockout
mice. These findings argue that 5-HT2
receptors couple through Gq proteins to
trigger a phospholipase C/inositol trisphosphate signaling cascade
resulting in the mobilization of intracellular
Ca2+, activation of calcineurin, and inhibition
of Cav1.2 L-type Ca2+
currents. This modulation and its blockade by atypical neuroleptics could have wide-ranging effects on synaptic integration and long-term gene expression in deep-layer prefrontal pyramidal neurons.
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