Redox Regulation of Neuronal Voltage-Gated Calcium Channels

Abstract

Significance: Voltage-gated calcium channels are ubiquitously expressed in neurons and are key regulators of cellular excitability and synaptic transmitter release. There is accumulating evidence that multiple subtypes of voltage-gated calcium channels may be regulated by oxidation and reduction. However, the redox mechanisms involved in the regulation of channel function are not well understood. Recent Advances: Several studies have established that both T-type and high-voltage-activated subtypes of voltage-gated calcium channel can be redoxregulated. This article reviews different mechanisms that can be involved in redox regulation of calcium channel function and their implication in neuronal function, particularly in pain pathways and thalamic oscillation. Critical Issues: A current critical issue in the field is to decipher precise mechanisms of calcium channel modulation via redox reactions. In this review we discuss covalent post-translational modification via oxidation of cysteine molecules and chelation of trace metals, and reactions involving nitric oxide-related molecules and free radicals. Improved understanding of the roles of redox-based reactions in regulation of voltage-gated calcium channels may lead to improved understanding of novel redox mechanisms in physiological and pathological processes. Future Directions: Identification of redox mechanisms and sites on voltage-gated calcium channel may allow development of novel and specific ion channel therapies for unmet medical needs. Thus, it may be possible to regulate the redox state of these channels in treatment of pathological process such as epilepsy and neuropathic pain. Antioxid. Redox Signal. 21, 880-891.

Redox regulation of the yeast voltage-gated Ca2+ channel homolog Cch1p by glutathionylation of specific cysteine residues

“…Thus, in higher organisms, different members of Ca 2+ -conducting ion channels/transporters are known to be redox sensitive (Kozai et al, 2014;Todorovic and Jevtovic-Todorovic, 2014). In the yeast Saccharomyces cerevisiae, it has recently been shown that the yeast vacuolar Ca 2+ channel Yvc1p, a member of the transient receptor potential (TRP) family of Ca 2+ channels, responds to the redox state in the cell to regulate Ca 2+ levels under conditions of glutathione depletion and extracellular oxidative stress through specific glutathionylation of cysteine residues (Chandel et al, 2016).…”

Novel ways to regulate T-type Ca2+ channels

“…In the peripheral nervous system, Ca V 3 are expressed in several types of sensory neurons, including a subpopulation of small, capsaicin-sensitive (presumed nociceptive) DRG neurons where they influence excitability and so play an important role in nociception. 6,8 Also due to their window currents, Ca V 3.1 and 3.2 strongly influence cell proliferation, as has been studied in vascular smooth muscle and different types of cancers (see 2 ).…”

“…Their control of burst firing in DRG neurons indicates they are of central importance to nociception since stimulus intensity correlates with burst frequency. 8 Native nociceptive and recombinant CaV3 currents are enhanced by reducing agents (which induce hyperalgesia) and inhibited by the oxidising agents. This sensitivity to redox modulation of Cav3.2 is specific among the Cav3 isoforms, and arises because of the presence of an extracellular, high affinity binding site for trace metals (Zn 2C , Ni 2C ) formed by interacting regions of the S1-S2 and S3-S4 loops within domain I of the channel protein.…”

“…Since reducing agents augment currents through Ca V 3.2 channels by relieving H191-dependent tonic Zn 2C inhibition, 8 we next explored a potential role for Zn 2C in the inhibitory effects of H 2 S. Consistent with previous studies, 7,8 we found that Zn 2C chelation using N,N, N',N'-tetra-2-picolylethylenediamine (TPEN) augmented Ca V 3.2 currents, an effect which could be reversed by submicromolar levels of Zn 2C , importantly suggesting that ambient levels of Zn 2C influences current amplitudes. Furthermore, Zn 2C chelation with TPEN fully reversed the H 2 S inhibition and led to a similar augmentation as was observed following TPEN application in the absence of H 2 S. Finally, H 2 S was ineffective in the continued presence of TPEN (i.e., in the absence of free extracellular Zn 2C ).…”

“…H 2 S might interact directly with the extracellular loop residues (including H191) which confer high affinity, or may act intracellularly to modify the channel at a distant but influential site, perhaps via sulfhydration or alternative modifications (see 4 ). It is also conceivable that metal binding site of Cav3.2 may serve as a convergence point for several types of signals, thus it was hypothesized that His191 may also bind other transition metals such as coper or iron which, in turn, may promote the metal-catalyzed oxidation (MCO) reaction at this site (see 8 ) providing the mechanism for redox modulation. Therefore, H 2 S and redox modulation of the channel may be mediated by different metals yet require a common site within the channel protein.…”