Parkinson

1
Parkinsons Disease
2
Illustrations from
Principles of Neural Science by E. R. Kandel,
J. H. Schwartz, and T. M. Jessell McGraw-Hill,
Fourth Edition, 2000 (Chapter
43) Figure 43-1 p. 854 Signaling between BG and
other parts Figure 43-2 p. 855 Basal ganglia and
nearby structures Figure 43-6 p. 861 Circuitry
in the system Figure 43-7 p. 863 Surgical
interventions
3
Articles on B.G., STN, Parkinsons
1 D. Terman, J. Rubin, A.C. Yew, and C.J.
Wilson, Activitiy patterns in a model of the
subthalamopallidal network of the basal
ganglia, J. Neurosci. 22 2963-2976, 2002. 2
D. Plenz and S.T. Kitai, A basal pacemaker
formed by the subthalamic nucleus and the
external globus pallidus, Nature 400
677-682, 1999.
4
Articles on B.G., STN, Parkinsons
3 A. Raz, E. Vaadia, and H. Bergman, Firing
patterns and correlations of spontaneous
discharge of pallidal neurons. , J.
Neurosci. 20 8559-8571, 2000. 4 P. Brown,
A. Oliviero, P. Mazzone, A. Isola, P. Tonali,
and V. DiLazzaro, Dopamine dependency of
oscillations between subthalamic nucleus and
pallidum in Parkinsons disease, J. Neurosci.
21 1033-1038, 2001.
5
1 Dependence on internal Ca2
In pituitary gonadotropes, GnRH induces rhythmic
oscillations in Ca2 concentrations. These
oscillations trigger exocytosis, releasing LH and
FSH into the circulatory system. Where is the
calcium that triggers the exocytosis coming
from? Does each increase in Ca2i trigger
exocytosis? In 1, Tse, et al., used high
temporal resolution capacitance measurements to
monitor cell membrane capacitance, DCm , and
measure Ca2i and DCm simultaneously.
6
1, Figure 1, page 82
7
Based on micrographs by others, they estimate
about 10,000 secretory vesicles in a single rat
gonadotrope, of which 600-1000 are within a
vesicle diameter of the cell membrane. They
estimate that more than 540 vesicles were
released in a single 10-second application of
GnHR. Increase in Ca2i is necessary for
exocytosis application of GnRH when the Ca2
is chelated does not produce exocytosis. Exocytos
is did occur when caged photolysis of IP3
triggered Ca2i without presence of GnRH.
When extracellular Ca2 was removed,
application of GnRH still produced both Ca2i
oscillations and exocytosis.
8
1 Conclusions
Hormone stimulated exocytosis is tightly coupled
to an oscillatory release of Ca2 from
intracellular stores that leads to micromolar
increases in Ca2i Each increase in Ca2i
can result in a burst of exocytosis Propose that
each Ca2i elevation rapidly releases the most
readily available vesicles, others are mobilized
during the decrease of Ca2i Oscillations of
Ca2i have the advantage of reducing toxic
effects of high Ca2i yet maintaining a
secretory output comparable to sustained
elevation of Ca2i
9
2 Local / global changes in Ca2i
Depending on the spatial relationship between the
intracellular stores of Ca2 and the site of
the exocytosis, the Ca2 signal can be very
local or spread through the entire cell. During
physiological stimulation, the average
concentration of the intracellular Ca2, Ca2i
seldom rises beyond a few mM, but in exocytosis,
the local concentration may rise to tens or
hundreds of mM. While formerly believed to not
be the case for release of Ca2 from
intracellular stores, this point of view is no
longer tenable.
10

First, more sensitive imaging has detected a
local gradient during release of Ca2 from
intracellular stores. Second, new studies of
Ca2 dependence of exocytosis show that low
levels of Ca2i are insufficient to trigger
exocytosis. intracellular stores. Pancreatic
acinar cells, pituitary gonadotropes, and
pituitary corticotropes behave differently in the
dependence on local gradients of Ca2i for
exocytosis.
11

When stimulated by GnRH, the anterior pituitary
gland secretes the reproductive hormones LH and
FSH. The GnRH acts via a G-protein coupled
receptor stimulating the release of Ca2 from IP3
sensitive stores. The peak Ca2i reaches 1 to
3 mM and exocytosis begins to occur when Ca2i
reaches .03mM and each burst of Ca2 triggers a
burst of exocytosis. By using the photolysis of
caged IP3 to trigger the release of the Ca2, it
is possible to more closely follow the rate of
exocytosis.
12

2, Figure 1, page 863
13

The study provides evidence that in the pituitary
gonadotropes, the IP3 sensitive stores are
probably quite close to the sites of exocytosis.
The fact that the rate of exocytosis falls before
the peak of the Ca2i is probably due to the
dissipation of the Ca2 away from the site of
exocytosis as the SERCA pumps start to operate
before the more general Ca2i has peaked.
Since the residual Ca2 must be cleared before
a second increase can begin, which expends energy
in the form of ATP to fuel the SERCA pumps, this
may lead to a more energy efficient mechanism for
hormone secretion.