High Effectiveness in Actions of Carfilzomib on Delayed-Rectifier K+ Current and on Spontaneous Action Potentials

Abstract

Carfilzomib (CFZ, Kyprolis®) is widely recognized as an irreversible inhibitor of proteasome activity; however, its actions on ion currents in electrically excitable cells are largely unresolved. The possible actions of CFZ on ionic currents and membrane potential in pituitary GH3, A7r5 vascular smooth muscle, and heart-derived H9c2 cells were extensively investigated in this study. The presence of CFZ suppressed the amplitude of delayed-rectifier K+ current (I K(DR)) in a time-, state-, and concentration-dependent manner in pituitary GH3 cells. Based on minimal reaction scheme, the value of dissociation constant for CFZ-induced open-channel block of I K(DR) in these cells was 0.33 µM, which is similar to the IC50 value (0.32 µM) used for its efficacy on inhibition of I K(DR) amplitude. Recovery from I K(DR) block by CFZ (0.3 µM and 1 µM) could be well fitted by single exponential with 447 and 645 ms, respectively. The M-type K+ current, another type of K+ current elicited by low-threshold potential, was slightly suppressed by CFZ (1 µM). Under current-clamp condition, addition of CFZ depolarized GH3 cells, broadened the duration of action potentials as well as raised the firing frequency. In A7r5 vascular smooth muscle cells or H9c2 cardiac cells, the CFZ-induced inhibition of I K(DR) remained efficacious. Therefore, our study led us to reflect that CFZ or other structurally similar compounds should somehow act on the activity of membrane KV channels through which they influence the functional activities in different types of electrically excitable cells such as endocrine, neuroendocrine cells, smooth muscle cells, or heart cells, if similar in vivo findings occur.

Evidence for the Effectiveness of Remdesivir (GS-5734), a Nucleoside-Analog Antiviral Drug in the Inhibition of IK(M) or IK(DR) and in the Stimulation of IMEP

“…Furthermore, the KCNQ2, KCNQ3, and KCNQ5 genes have been noticed to encode the main subunits of K V 7.2, K V 7.3, and K V 7.5 channels, respectively; and among them, the augmented activity produces the M-type K + current (I K(M) ), which is characterized by a slowly activating and deactivating property (Brown and Adams, 1980;Sankaranarayanan and Simasko, 1996;Wang et al, 1998;Selyanko et al, 1999;Shu et al, 2007;Lu et al, 2019;So et al, 2019;Yang et al, 2019). With growing recognition, targeting I K(M) is regarded as a treatment of various neurologic diseases.…”

“…The voltage-gated K + (K V ) channels are essential in determining the membrane excitability in electrically excitable or non-excitable cells. Specifically, K V 3 (KCNC) and K V 2 (KCNB), two delayed-rectifier K + channels, are widespread in different excitable cells such as endocrine cells ( Lien and Jonas, 2003 ; Wang et al., 2008 ; Fletcher et al., 2018 ; Kuo et al., 2018 ; Lu et al., 2019 ; So et al., 2019 ). The causal link between the delayed-rectifier K + current ( I K(DR) ) and K V 3/K V 2 channels has been previously disclosed ( Yeung et al., 2005 ; Wang et al., 2008 ; Huang et al., 2013 ; Chang et al., 2019 ; Lu et al., 2019 ).…”

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

“…Voltage-gated K + (K V ) channels play essential roles in determining membrane excitability, and the delayed rectifier K + channels, such as K V 3 (KCNC) and K V 2 (KCNB) channels, are ubiquitous in endocrine cells [21][22][23][24]. A causal relationship between the K V 3 or K V 2 channel and the delayed rectifier K + current (I K(DR) ) has been previously established [21,23,25,26].…”

“…This current is characterized by a mixed inward Na + /K + one with a slowly activating property during long-lasting membrane hyperpolarization, and it is subject to being blocked by various compounds, such as CsCl, ivabradine, and zatebradine [9,14-19].As described in a number of previous studies [7,9,10,[12][13][14], the increased amplitude of I h can act to depolarize membrane potential to the threshold required for elicitation of the action potential in electrically excitable cells. This type of ionic current has been regarded to be carried by channels of the hyperpolarization-activated cyclic nucleotide-gated (HCN1-4) gene family, which belongs to the superfamily of voltage-gated K + channels and cyclic nucleotide-gated channels [8,12,18,20].Voltage-gated K + (K V ) channels play essential roles in determining membrane excitability, and the delayed rectifier K + channels, such as K V 3 (KCNC) and K V 2 (KCNB) channels, are ubiquitous in endocrine cells [21][22][23][24]. A causal relationship between the K V 3 or K V 2 channel and the delayed rectifier K + current (I K(DR) ) has been previously established [21,23,25,26].…”

“…A causal relationship between the K V 3 or K V 2 channel and the delayed rectifier K + current (I K(DR) ) has been previously established [21,23,25,26]. The K V channels from the K V 3.1-K V 3.2 types, the biophysical properties of which exhibit to have positively shifted voltage dependency and fast deactivation rate, are the major determinants of I K(DR) identified in the pituitary tumor (GH 3 ) cells [23,24,26]. However, to the best of our knowledge, whether and how CIL or other structurally similar compounds affect any modifications on these types of K + currents (e.g., I K(DR) ) remains largely unexplored.Therefore, in light of the above-described considerations, we intended to address the possibility that CIL exerts the perturbing actions on different types of ionic currents, which include hyperpolarization-activated cation current (I h ), delayed-rectifier K + current (I K(DR) ), and voltage-gated Na + current (I Na ) identified in pituitary tumor (GH 3 ) cells.…”