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Parkinson’s Disease

Parkinson’s Disease. 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

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Parkinson’s Disease

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  1. Parkinson’s 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, & Parkinson’s [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, & Parkinson’s [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 Parkinson’s 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 [Ca2+]i trigger exocytosis? In [1], Tse, et al., used high temporal resolution capacitance measurements to monitor cell membrane capacitance, DCm , and measure [Ca2+]i 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 [Ca2+]i is necessary for exocytosis: application of GnRH when the Ca2+ is chelated does not produce exocytosis. Exocytosis did occur when caged photolysis of IP3 triggered [Ca2+]i without presence of GnRH. When extracellular Ca2+ was removed, application of GnRH still produced both [Ca2+]i 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 [Ca2+]i Each increase in [Ca2+]i can result in a burst of exocytosis Propose that each [Ca2+]i elevation rapidly releases the most readily available vesicles, others are mobilized during the decrease of [Ca2+]i Oscillations of [Ca2+]i have the advantage of reducing toxic effects of high [Ca2+]i yet maintaining a secretory output comparable to sustained elevation of [Ca2+]i

  9. [2] Local / global changes in [Ca2+]i 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+, [Ca2+]i 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 [Ca2+]i are insufficient to trigger exocytosis. intracellular stores. Pancreatic acinar cells, pituitary gonadotropes, and pituitary corticotropes behave differently in the dependence on local gradients of [Ca2+]i 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 [Ca2+]i reaches 1 to 3 mM and exocytosis begins to occur when [Ca2+]i 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 [Ca2+]i 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 [Ca2+]i 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.

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