Verapamil Block of T-Type Calcium Channels

Abstract

Verapamil is a prototypical phenylalkylamine (PAA), and it was the first calcium channel blocker to be used clinically. It tonically blocks L-type channels in the inner pore with micromolar affinity, and its affinity increases at depolarized membrane potentials. In T-type calcium channels, verapamil blocks with micromolar affinity and has modestly increased affinity at depolarized potentials. We found that a related PAA, 4-desmethoxyverapamil (D888), is comparable with verapamil both in affinity and in state-dependence. Permanently charged verapamil was more effective intracellularly than neutral verapamil. Charged PAAs were able to access their binding site from both inside and outside the cell. Furthermore, membrane-impermeant [2-(trimethylammonium)ethyl]methanethiosulfonate was able to access the inner pore from outside of the cell. We examined a homology model of the T-type calcium channel to look for possible routes of drug entry. Mutation of L1825W produced a channel that was blocked significantly more slowly by charged verapamil from the outside, with an increase in apparent affinity when the drug was applied from the inside. Data suggest that T-type channels have a back pathway through which charged drugs can access the inner pore of the channel without passing through the plasma membrane.

Intranasal Administration as a Route for Drug Delivery to the Brain: Evidence for a Unique Pathway for Albumin

“…[ 125 I]Alb uptake. The same was true of verapamil, the L-and T-type Ca 1 channel blocker (Bergson et al, 2011), which can also inhibit P-glycoprotein, an ATP-dependent drug transport protein (Schinkel, 1999). Albumin-binding proteins, such as endothelial membrane-associated gp60 (albondin) (Schnitzer, 1992), use caveolae-dependent mechanisms to transport albumin from peripheral blood vessel lumen to interstitium and are inhibited by filipin (Schnitzer et al, 1994;Tiruppathi et al, 1997), a cholesterol-binding agent that inhibits caveolaedependent transcytosis (Schnitzer et al, 1994).…”

Calcium Ions Released from Mineral Trioxide Aggregate are Taken Up by C2C12 Cells via the L-Type Voltage-Dependent Calcium Channel

“…Moreover, it has been reported that verapamil blocks T-type voltage-dependent calcium channels 30) . In the future, we will clarify the details of the influx of calcium ions into C2C12 cells during depolarization, using not only verapamil but also another type of calcium channel blocker.…”

Mechanism of Action, Efficacy, and Adverse Events of Calcium Antagonists in Hypertrophic Scars and Keloids

“…Currently, verapamil is used in clinical setting to terminate cardiac arrhythmias. 41,42 It is reported that calcium antagonists promote a change in cell shape from bipolar to spherical. The mechanism by which this is accomplished remains unknown.…”