The long term objective of this proposal is to understand the role of the voltage dependent calcium channel in the excitability and function of central cardiovascular neurons that control blood pressure. The cell type of major interest are single dispersed neurons from the nucleus tractus solitarius (NTS) of guinea pig brain. We will also investigate the properties of calcium channels in the GH3 rat anterior pituitary cell line. These two cell types have very similar calcium currents that are unusual in that these currents contain two distinct components. Each component has a different activation threshold and very different inactivation time constants. The advantage of GH3 cells is that they are readily available and thus more convenient for many aspects of this project.
The specific aims of this proposal are: 1) to examine the properties of the two distinct Ca currents at the whole cell and single channel by patch voltage clamp techniques, 2) to examine the specificites and mechanisms of actions of a wide variety of pharmacological agents that are known to affect Ca++ channel function, 3) to examine modulation of the two types of Ca++ currents by intracellular messengers and metabolites and 4) to examine the role of the two types of Ca++ channels in controlling the frequency of firing and the shape of the action potential by recording from cells under current clamp conditions. This information is important for understanding the way in which neuronal and neuroendocrine cells function. Finally, since Ca++ channel antagonists have recently gained widespread use for the treatment of cardiovascular disease, a knowledge of their potency and mechanism of action on CNS cells is important in order to assess the toxic or side effects of these drugs. The action of Ca++ channel antagonists on the NTS neurons is also of therapeutic interest since these neurons play an important role in the regulation of blood pressure via modulation of baroreceptor activity.
|Kunze, D L; Ritchie, A K (1990) Multiple conductance levels of the dihydropyridine-sensitive calcium channel in GH3 cells. J Membr Biol 118:171-8|
|Keahey, H H; Boyd 3rd, A E; Kunze, D L (1989) Catecholamine modulation of calcium currents in clonal pancreatic beta-cells. Am J Physiol 257:C1171-6|
|Colden-Stanfield, M; Schilling, W P; Ritchie, A K et al. (1987) Bradykinin-induced increases in cytosolic calcium and ionic currents in cultured bovine aortic endothelial cells. Circ Res 61:632-40|
|Kunze, D L (1987) Calcium currents of cardiovascular neurons isolated from adult guinea pigs. Am J Physiol 252:H867-71|