Drug Targets in the Voltage-Gated Calcium Channel Family: Why Some Are and Some Are Not

Abstract

The L-type calcium channel antagonists have been, and continue to be, a very successful group of therapeutic agents targeted at cardiovascular disorders, notably angina and hypertension. The discovery that the voltage-gated calcium channels are a large and widely distributed family with important roles in both the peripheral and central nervous systems has initiated a major search for drugs active at other calcium channel types directed at disorders of the central nervous system, including pain, epilepsy, and stroke. These efforts have not been therapeutically successful thus far, and small molecule equivalents of the L-type blockers nifedipine, diltiazem, and verapamil directed at non-L-type channels have not been found. The underlying reasons for this are discussed together with suggestions for new directions, including fertility control, oxygen-sensitive channels, and calcium channel activators.

ATP and purinergic receptor–dependent membrane traffic in bladder umbrella cells

“…We also observed that verapamil and dipyridamole significantly impaired ATP release, which implicates ABC and nucleoside transporters. However, verapamil acts on other targets including L-type Ca 2+ channels (36). These latter results are in contrast to those of a previous study that found no effect of verapamil or dipyridamole on ATP release from guinea pig ureter epithelium (7) and may reflect species differences or differences in ureter versus bladder epithelium.…”

“…Glibenclamide, a blocker of some ion ABC proteins such as the CFTR and sulfonylurea receptors (33,34), had no significant effect on serosal ATP release but did cause a decrease in mucosal ATP release (Figure 1, A and B). Verapamil, an inhibitor of several additional ABC proteins (35) and L-type Ca 2+ channels (36), and dipyridamole, an inhibitor of nucleoside transporters (37), caused significant inhibition of both serosal and mucosal ATP release ( Figure 1, A and B). No ATP release was observed when the uroepithelium was first removed by gentle scraping before the underlying submucosa was mounted and exposed to pressure (Figure 1, A and B), which confirms that the uroepithelium was the source Figure 1 ATP localization, release, and hydrolysis in uroepithelium.…”

Ca2+ entry-independent effects of L-type Ca2+ channel modulators on Ca2+ sparks in ventricular myocytes

“…Contrarily, verapamil, which binds to the site of phenylalkilamines and does not affect the DHPR inactivation process, was without effect (31). An increase in spark frequency was found with a DHPR agonist (BayK) that interacts with the dihydropyridine site (50,51) and also with FPL, which appears to have a different mechanism of action and involves binding to a novel benzolpyrrole site (50). We did not test all other available classes of DHPR modulators.…”

“…In intact cells, direct effects of nifedipine on Ca 2ϩ sparks were not found; however, nifedipine inhibited the action of BayK (23,44). The differential effect of nifedipine may be related to the preferred binding of this compound to the open or inactivated conformations of the DHPR, which are favored when the membrane potential collapses (as in permeabilized cells) (22,31,50,51). At Ϫ80 mV (as in intact cells), DHPR channels are mostly in the closed state, which has a much lower affinity for nifedipine.…”

“…1A, we show the effect of nifedipine, an antagonist of the DHPR, on Ca 2ϩ sparks. Nifedipine binds to specific sites on the DHPR, known as "dihydropyridine sites" (50,51). Representative confocal linescan images of Ca 2ϩ sparks and plots of F/F 0 from selected subcellular regions are shown in In Fig.…”