Kvβ1.3 Reduces the Degree of Stereoselective Bupivacaine Block of Kv1.5 Channels

Abstract

The degree of stereoselective block of Kv1.5 decreases from 9 to 4 when Kvbeta1.3 is present. L510 is determinant for the modulation of bupivacaine block, because it is the only residue of the S6 segment that binds to both bupivacaine and Kvbeta1.3. These findings support an overlapping binding site for drugs and Kvbeta1.3.

Assessment of beating parameters in human induced pluripotent stem cells enables quantitative in vitro screening for cardiotoxicity

“…For example, bupivacaine, a Na + blocker, exhibited a profile different from other Na + blockers, including the appearance of wide peaks. Such a phenotype is consistent with K + blocking and, in fact, bupivacaine has been shown to have such an effect in the literature (Arias et al , 2007). As another example, the anti-inflammatory drug dichlophenac had a very similar profile to Na + channel blockers and, in fact, Na + blocking is a known side effect for this compound (Gwanyanya et al , 2012).…”

Irvalec Inserts into the Plasma Membrane Causing Rapid Loss of Integrity and Necrotic Cell Death in Tumor Cells

“…During the appearance of Irvalec effects, a downward effect of the current during the application of the ramp protocol was also observed (white arrows). This type of effect is also observed when Kv1.5 channels are co-expressed with the Kvβ1.3 subunit that induces a fast and incomplete inactivation of the current [14], [19]–[21]. Also as shown in Figure 3C, the time effects of Irvalec appeared within two phases, due to the observed downward effect.…”

Protein Kinase C (PKC) Activity Regulates Functional Effects of Kvβ1.3 Subunit on KV1.5 Channels

“…For the electrophysiological experiments, cells were transfected with K v 1.5 (0.4 g) or K v 1.5ϩK v ␤1.3 channels (0.3 g) and a reporter plasmid expressing CD8 (1.6 g) using Lipofectamine 2000 (10 l) (Invitrogen). Before experimental use, the cells were incubated with polystyrene microbeads precoated with an anti-CD8 antibody (Dynabeads M450, Dynal) as described previously (5,7,42). For the immunocytochemistry and immunoprecipitation studies, the cells were cotransfected with 0.5 g of K v 1.5 or K v 2.1-HA and 1 g of K v ␤1.3-Myc cDNA.…”

“…However, depolarization to ؉100 mV revealed K v ␤1. The outward potassium current I Kur , 7 the main current responsible for human atrial repolarization, is generated following the activation of K v 1.5 channels. The slow and partial inactivation and the voltage dependence of these channels underlie their key role in the regulation of the atrial action potential duration (1,2).…”

“…This slow inactivation is modified by the assembly of K v 1.5 subunits with ␤ subunits (K v ␤1.2, K v ␤1.3, and K v ␤2.1) present in the human myocardium (3,4). The K v ␤1.3 subunit provides a number of functions, including a fast, partial inactivation component, a greater degree of slow inactivation, a shift of the activation curve toward more negative potentials, a 7-fold decrease in the sensitivity of the channel to the block induced by antiarrhythmic drugs and local anesthetics, and a decrease in the degree of stereoselective blockage (5)(6)(7).…”