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The Journal of Neurophysiology Vol. 83 No. 4 April 2000, pp. 2332-2348
Copyright ©2000 by the American Physiological Society
1Department of Biological Sciences and Program in Neuroscience, Biomedical Research Facility, Florida State University, Tallahassee, Florida 32306; and 2Zoology and Wildlife Sciences, Auburn University, Auburn, Alabama 36849-5414
Fadool, D. A.,
K. Tucker,
J. J. Phillips, and
J. A. Simmen.
Brain Insulin Receptor Causes Activity-Dependent Current
Suppression in the Olfactory Bulb Through Multiple Phosphorylation of
Kv1.3. J. Neurophysiol. 83: 2332-2348, 2000. Insulin and insulin receptor (IR) kinase are found in abundance in
discrete brain regions yet insulin signaling in the CNS is not
understood. Because it is known that the highest brain insulin-binding
affinities, insulin-receptor density, and IR kinase activity are
localized to the olfactory bulb, we sought to explore the downstream
substrates for IR kinase in this region of the brain to better
elucidate the function of insulin signaling in the CNS. First, we
demonstrate that IR is postnatally and developmentally expressed in
specific lamina of the highly plastic olfactory bulb (OB). ELISA
testing confirms that insulin is present in the developing and adult
OB. Plasma insulin levels are elevated above that found in the OB,
which perhaps suggests a differential insulin pool. Olfactory bulb
insulin levels appear not to be static, however, but are elevated as
much as 15-fold after a 72-h fasting period. Bath application of
insulin to cultured OB neurons acutely induces outward current
suppression as studied by the use of traditional whole-cell and
single-channel patch-clamp recording techniques. Modulation of OB
neurons is restricted to current magnitude; IR kinase activation does
not modulate current kinetics of inactivation or deactivation.
Transient transfection of human embryonic kidney cells with cloned
Kv1.3 ion channel, which carries a large proportion of the outward
current in these neurons, revealed that current suppression was the
result of multiple tyrosine phosphorylation of Kv1.3 channel. Y to F
single-point mutations in the channel or deletion of the kinase domain
in IR blocks insulin-induced modulation and phosphorylation of Kv1.3.
Neuromodulation of Kv1.3 current in OB neurons is activity dependent
and is eliminated after 20 days of odor/sensory deprivation induced by
unilateral naris occlusion at postnatal day 1. IR kinase but not Kv1.3
expression is downregulated in the OB ipsilateral to the occlusion, as
demonstrated in cryosections of right (control) and left
(sensory-deprived) OB immunolabeled with antibodies directed against
these proteins, respectively. Collectively, these data support the
hypothesis that the hormone insulin acts as a multiply functioning
molecule in the brain: IR signaling in the CNS could act as a
traditional growth factor during development, be altered during energy
metabolism, and simultaneously function to modulate electrical activity
via phosphorylation of voltage-gated ion channels.
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