Differential zinc permeation and blockade of L-type Ca2+ channel isoforms Cav1.2 and Cav1.3

Abstract

Certain voltage-activated Ca2+ channels have been reported to act as potential zinc entry routes. However, it remains to be determined whether zinc can permeate individual Ca2+ channel isoforms. We expressed recombinant Ca2+ channel isoforms in Xenopus oocytes and attempted to record zinc currents from them using a two-electrode voltage clamp method. We found that, in an extracellular zinc solution, inward currents arising from zinc permeation could be recorded from Xenopus oocytes expressing L-type Cav1.2 or Cav1.3 isoforms, but not from oocytes expressing Cav2.2, Cav2.3, Cav3.1, or Cav3.2. Zinc currents through Cav1.2 and Cav1.3 were blocked by nimodipine, but enhanced by (±)Bay K8644, supporting the finding that zinc can permeate both L-type Cav1.2 and Cav1.3 channel isoforms. We also examined the blocking effects of low concentrations of zinc on Ca2+ currents through the L-type channel isoforms. Low micro-molar zinc potently blocked Ca2+ currents through Cav1.2 and Cav1.3 with different sensitivities (IC50 for Cav1.2 and Cav1.3=18.4 and 34.1 μM) and de-accelerated the activation and inactivation kinetics in a concentration-dependent manner. Notably, mild acidifications of the external zinc solution increased zinc currents through Cav1.2 and Cav1.3, with the increment level for Cav1.3 being greater than that for Cav1.2. In overall, we provide evidence that Cav1.2 and Cav1.3 isoforms are capable of potentially functioning as zinc permeation routes, through which zinc entry can be differentially augmented by mild acidifications.

Zn2+-induced changes in Cav2.3 channel function: An electrophysiological and modeling study

“…11, D-E). Taken together, these findings are in good agreement with previous studies showing that Zn 2+ and other d-block metal ions slow activation, often without altering channel voltage dependence, in several VGCCs lacking critical histidine residues in domain I (Magistretti et al, 2001Castelli et al, 2003;Park et al, 2015). Interestingly, most of these studies also found a less marked but significant metalinduced slowing of I Ca deactivation speed Castelli et al, 2003), an effect that was also observed in the present study (Fig.…”

The Involvement of CaV1.3 Channels in Prolonged Root Reflexes and Its Potential as a Therapeutic Target in Spinal Cord Injury

“…Its inhibitory effect against hyperexcitablity on calcium influx is also under investigation for other neurological diseases such as Parkinson's and multiple sclerosis (Guzman et al, 2010;Ingwersen et al, 2018). However, nimodipine is a non-selective L-type calcium channel blocker with higher potency for Ca V 1.2 than Ca V 1.3 (Park et al, 2015). Thus, its side effects on the cardiovascular system may diminish its therapeutic application (Kang et al, 2012).…”

Zinc as Allosteric Ion Channel Modulator: Ionotropic Receptors as Metalloproteins

“…This metal modulates negatively the heart T-type Ca 2+ channels with zinc IC 50 s of 81.7, 0.78 and 158.6 µM [ 82 ] or 196.1, 24.1 and 152.2 µM [ 83 ] for Cav3.1, Cav3.2 and Cav3.3, respectively. Regarding the N-type calcium channel, mainly expressed in neurons, zinc modulates Cav2.2 with an IC 50 of 98 µM, the P/Q-type Cav2.1 with an IC 50 of 110 µM, the R-type Cav2.3 with an IC 50 of 31.8 µM, and the L-type Ca 2+ channels (expressed mainly in smooth muscle cells) Cav1.2 with an IC 50 of 10.9 [ 83 ] or 18.4 µM; and Cav1.3 with an IC 50 of 34.1 µM [ 84 ]. In addition, intracellular zinc blocks the calcium-activated currents in the calcium-activated chloride channel (TMEM16A) with an IC 50 of 12.5 µM [ 85 ].…”