Structural Determinants of the High Affinity Extracellular Zinc Binding Site on Cav3.2 T-type Calcium Channels

Kang, Ho-Won; Vitko, Iuliia; Lee, Sang-Soo; Perez‐Reyes, Edward; Lee, Jung-Ha

doi:10.1074/jbc.m109.067660

Cited by 44 publications

(62 citation statements)

References 42 publications

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“…They appear to be involved in the inhibition of Cav2.3 by Ni + ions [16] and application of Ni + to Cav2.1-or Cav2.3-expressing Xenopus oocytes produces a dosedependent shift of Va that is reminiscent of the Va changes produced by pHo variations [35]. The equivalent histidine residue in Cav3.2 defines, with the neighboring aspartate and glycine residues, a metal binding site implicated in the Ni + and Zn 2+ inhibition of this channel [17,18]. Metal chelation inhibits the gating charges and therefore the S4 movement and the subsequent pore opening [18].…”

Section: Discussionmentioning

confidence: 96%

Two sets of amino acids of the domain I of Cav2.3 Ca2+ channels contribute to their high sensitivity to extracellular protons

Cens

Rousset

Charnet

2011

Pflugers Arch - Eur J Physiol

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Extracellular acidification decreases Ca(2+) current amplitude and produces a depolarizing shift in the activation potential (Va) of voltage-gated Ca(2+) channels (VGCC). These effects are common to all VGCC, but differences exist between Ca(2+) channel types and the underlying molecular mechanisms remain largely unknown. We report here that the changes in current amplitude induced by extracellular acidification or alkalinisation are more important for Cav2.3 R type than for Cav2.1 P/Q-type Ca(2+) channels. This difference results from a higher shift of Va combined with a modification of channel conductance. Although involved in the sensitivity of channel conductance to extracellular protons, neither the EEEE locus nor the divalent cation selectivity locus could explain the specificity of the pH effects. We show that this specificity involves two separate sets of amino acids within domain I of the Cavα subunit. Residues of the voltage sensor domain and residues in the pore domain mediate the effects of extracellular protons on Va and on channel conductance, respectively. These new insights are important for elucidating the molecular mechanisms that control VGCC gating and conductance and for understanding the role of extracellular protons in other channels or membrane-tethered enzymes with similar pore and/or voltage sensor domains.

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Section: Discussionmentioning

confidence: 96%

Two sets of amino acids of the domain I of Cav2.3 Ca2+ channels contribute to their high sensitivity to extracellular protons

Cens

Rousset

Charnet

2011

Pflugers Arch - Eur J Physiol

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“…Furthermore, molecular mutagenesis studies have shown that histidine 191 in repeat I of Ca V3.2 is critical for the action of reducing agents that chelate off endogenously bound divalent metal ions (e.g. Zn 2+ ), which appears to exert tonic inhibition of T-channels both in vitro and in vivo (Nelson et al, 2007b;Kang et al, 2010). A related phenomenon was recently described for gaseous transmitter hydrogen sulfide (H2S), an endogenous compound formed from L-cysteine.…”

Section: Redox Modulationmentioning

confidence: 99%

T‐type voltage‐gated calcium channels as targets for the development of novel pain therapies

Todorović

Jevtović-Todorović

2011

British J Pharmacology

152

135

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It is well recognized that voltage‐gated calcium (Ca2+) channels modulate the function of peripheral and central pain pathways by influencing fast synaptic transmission and neuronal excitability. In the past, attention focused on the modulation of different subtypes of high‐voltage‐activated‐type Ca2+ channels; more recently, the function of low‐voltage‐activated or transient (T)‐type Ca2+ channels (T‐channels) in nociception has been well documented. Currently, available pain therapies remain insufficient for certain forms of pain associated with chronic disorders (e.g. neuropathic pain) and often have serious side effects. Hence, the identification of selective and potent inhibitors and modulators of neuronal T‐channels may help greatly in the development of safer, more effective pain therapies. Here, we summarize the available information implicating peripheral and central T‐channels in nociception. We also discuss possible future developments aimed at selective modulation of function of these channels, which are highly expressed in nociceptors.

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“…an Asp-Glu-His motif in repeat IS3-IS4 and a second aspartate residue in IS2 (27). It has been proposed that the metal-binding site stabilizes a closed conformation of the voltage-sensor in repeat I of Ca V 3.2 and consequently inhibits channel opening.…”

Section: Todorovic and Jevtovic-todorovicmentioning

confidence: 99%

Redox Regulation of Neuronal Voltage-Gated Calcium Channels

TodorovicSlobodan

Jevtovic-TodorovicVesna

2014

Antioxidants & Redox Signaling

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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.

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Structural Determinants of the High Affinity Extracellular Zinc Binding Site on Cav3.2 T-type Calcium Channels

Cited by 44 publications

References 42 publications

Two sets of amino acids of the domain I of Cav2.3 Ca2+ channels contribute to their high sensitivity to extracellular protons

Two sets of amino acids of the domain I of Cav2.3 Ca2+ channels contribute to their high sensitivity to extracellular protons

T‐type voltage‐gated calcium channels as targets for the development of novel pain therapies

Redox Regulation of Neuronal Voltage-Gated Calcium Channels

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