Nelson, M.T., Joksovic, P.M., Perez-Reyes, E. & Todorovic, S.M. The endogenous redox agent L-cysteine induces T-type Ca2+ channel-dependent sensitization of a novel subpopulation of rat peripheral nociceptors. J. Neurosci. 25, 8766-8775

ArticleinThe Journal of Neuroscience : The Official Journal of the Society for Neuroscience 25(38):8766-75 · October 2005with5 Reads
DOI: 10.1523/JNEUROSCI.2527-05.2005 · Source: PubMed
Abstract
Recent studies have demonstrated a previously unrecognized contribution of T-type Ca2+ channels in peripheral sensory neurons to pain sensation (nociception). However, the cellular mechanisms underlying the functions of these channels in nociception are not known. Here, in both acutely dissociated and intact rat dorsal root ganglion neurons, we characterize a novel subpopulation of capsaicin- and isolectin B4-positive nociceptors that also expresses a high density of T-type Ca2+ currents. Using these "T-rich" cells as a model, we demonstrate that the endogenous reducing agent L-cysteine lowers the threshold for nociceptor excitability and induces burst firing by increasing the amplitude of T-type currents and shifting the gating parameters of T-type channels. These findings, which provide the first direct evidence of T-type Ca2+ channel involvement in the control of nociceptor excitability, suggest that endogenous T-type channel agonists may sensitize a unique subpopulation of peripheral nociceptors, consequently influencing pain processing under normal or pathological conditions.
    • "3) The biophysical properties of I NaI were not consistent with those of inactivating T-type Ca 2 currents. I NaI inactivated with a time constant of 300 s at 0 mV and was half-inactivated at approximately 100 mV (Table 2), in contrast to T-type Ca 2 currents, which have inactivation time constants ranging from ten to hundreds of milliseconds (depending on voltage and subunit) and V inact values from 47 to 86 mV (Coulter et al. 1989; Monteil et al. 2000; Chemin et al. 2001; Gomora et al. 2002; Díaz et al. 2005; Nelson et al. 2005; Vitko et al. 2005; Emerick et al. 2006; Zhong et al. 2006). The fast inactivation of L-type Ca 2 current is relatively slow, with time constants of 15 ms or more (Beuckelmann et al. 1991; Mewes and Ravens 1994; Magyar et al. 2000) and is Ca 2 dependent, with reduced extent and speed of inactivation when Ba 2 or Na (in M Ca 2 ) is the charge carrier (Brehm and Eckert 1978; Lee et al. 1985; Ferreira et al. 2003; Brunet et al. 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Firing patterns differ between sub-populations of vestibular primary afferent neurons. The role of sodium (NaV) channels in this diversity has not been investigated because NaV currents in rodent vestibular ganglion neurons (VGNs) were reported to be homogeneous, with the voltage dependence and tetrodotoxin (TTX) sensitivity of most neuronal NaV channels. RT-PCR experiments, however, indicated expression of diverse NaV channel subunits in the vestibular ganglion, motivating a closer look. Whole-cell recordings from acutely dissociated postnatal VGNs confirmed that nearly all neurons expressed NaV currents that are TTX-sensitive and have activation midpoints between −30 mV and −40 mV. In addition, however, many VGNs expressed one of two other NaV currents. Some VGNs had a small current with properties consistent with NaV1.5 channels: low TTX sensitivity, sensitivity to divalent cation block, and a relatively negative voltage range, and some VGNs showed NaV1.5-like immunoreactivity. Other VGNs had a current with the properties of NaV1.8 channels: high TTX resistance, slow time course, and a relatively depolarized voltage range. In two NaV1.8 reporter lines, subsets of VGNs were labeled. VGNs with NaV1.8-like TTX-resistant current also differed from other VGNs in the voltage dependence of their TTX-sensitive currents and in the voltage threshold for spiking and action potential shape. Regulated expression of NaV channels in primary afferent neurons is likely to selectively affect firing properties that contribute to the encoding of vestibular stimuli.
    Full-text · Article · Mar 2016
    • "In vivo studies have revealed that many of these H191-dependent modulators of Cav3.2 channels have marked effects on pain (Evans & Todorovic, 2015). For example, zinc was shown to have antinociceptive properties (Garabedian et al., 1996; Liu et al., 1999; Nozaki et al., 2011), while reducing agents L-cysteine and DTT, as well as the zinc chelator TPEN display pronociceptive properties (Nelson et al., 2005; Kawabata et al., 2007; Nelson et al., 2007b; Matsunami et al., 2011). The possibility that these effects are mediated through Cav3.2 channel modulation has been explored using knock-out animals (Choi et al., 2007; Nelson et al., 2007b). "
    [Show abstract] [Hide abstract] ABSTRACT: Cav3.2 channels are T-type voltage-gated calcium channels that play important roles in controlling neuronal excitability, particularly in dorsal root ganglia (DRG) neurons where they are involved in touch and pain signaling. Cav3.2 channels are modulated by low concentrations of metal ions (nickel, zinc) and redox agents, which involves the histidine 191 (H191) in the channel's extracellular IS3-IS4 loop. It is hypothesized that this metal/redox modulation would contribute to the tuning of the excitability properties of DRG neurons. However, the precise role of this H191-dependent modulation of Cav3.2 channel remains unresolved. Towards this goal, we have generated a knock-in (KI) mouse carrying the mutation H191Q in the Cav3.2 protein. Electrophysiological studies were performed on a subpopulation of DRG neurons, the D-hair cells, which express large Cav3.2 currents. We describe an impaired sensitivity to zinc, nickel and ascorbate of the T-type current in D-hair neurons from KI mice. Analysis of the action potential (AP) and low-threshold calcium spike (LTCS) properties revealed that, contrary to that observed in WT D-hair neurons, a low concentration of zinc and nickel is unable to modulate i) the rheobase threshold current, ii) the afterdepolarization (ADP) amplitude, iii) the threshold potential necessary to trigger a LTCS and iv) the LTCS amplitude in D-hair neurons from KI mice. Altogether, our data demonstrate that this H191-dependent metal/redox regulation of Cav3.2 channels can tune neuronal excitability. This study validates the use of this Cav3.2-H191Q mouse model for further investigations of the physiological roles thought to rely on this Cav3.2 modulation. This article is protected by copyright. All rights reserved
    Full-text · Article · Mar 2016
    • "Sensitivity to these agents was exploited in order to demonstrate the importance of Cav3.2 in nociception: hindpaw injections of DTT or L-cysteine induces thermal and mechanical hyperalgesia (Todorovic et al., 2001), and such effects are prevented with the Ca 2+ channel inhibitor mibefradil; furthermore, analgesic effects are observed with DTNB (Todorovic et al., 2001). Such findings were confirmed in a subpopulation of nociceptive neurons expressing high levels of Cav3 channels (Nelson et al., 2005). An important breakthrough in the field was achieved by the joint work of Perez-Reyes' and Lee's groups which allowed the characterization of specific Cav3.2 "
    [Show abstract] [Hide abstract] ABSTRACT: Ion channels represent a large and growing family of target proteins regulated by gasotransmitters such as nitric oxide, carbon monoxide and, as described more recently, hydrogen sulfide. Indeed, many of the biological actions of these gases can be accounted for by their ability to modulate ion channel activity. Here, we report recent evidence that H2 S is a modulator of low voltage-activated T-type Ca(2+) channels, and discriminates between the different subtypes of T-type Ca(2+) channel in that it selectively modulates Cav3.2, whilst Cav3.1 and Cav3.3 are unaffected. At high concentrations, H2 S augments Cav3.2 currents, an observation which has led to the suggestion that H2 S exerts its pro-nociceptive effects via this channel, since Cav3.2 plays a central role in sensory nerve excitability. However, at more physiological concentrations, H2 S is seen to inhibit Cav3.2. This inhibitory action requires the presence of the redox-sensitive, extracellular region of the channel which is responsible for tonic metal ion binding, and which particularly distinguishes this channel isoform from Cav3.1 and 3.3. Further studies indicate that H2 S may act in a novel manner to alter channel activity by potentiating the zinc sensitivity / affinity of this binding site. This review discusses the different reports of H2 S modulation of T-type Ca(2+) channels, and how such varying effects may impact on nociception, given the role of this channel in sensory activity. This subject remains controversial, and future studies are required before the impact of T-type Ca(2+) channel modulation by H2 S might be exploited as a novel approach to pain management. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jan 2016
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