The Upregulation of α₂δ-1 Subunit Modulates Activity-Dependent Ca²⁺Signals in Sensory Neurons

Abstract

As auxiliary subunits of voltage-gated Ca 2ϩ channels, the ␣ 2 ␦ proteins modulate membrane trafficking of the channels and their localization to specific presynaptic sites. Following nerve injury, upregulation of the ␣ 2 ␦-1 subunit in sensory dorsal root ganglion neurons contributes to the generation of chronic pain states; however, very little is known about the underlying molecular mechanisms. Here we show that the increased expression of ␣ 2 ␦-1 in rat sensory neurons leads to prolonged Ca 2ϩ responses evoked by membrane depolarization. This mechanism is coupled to Ca V 2.2 channel-mediated responses, as it is blocked by a -conotoxin GVIA application. Once initiated, the prolonged Ca 2ϩ transients are not dependent on extracellular Ca 2ϩ and do not require Ca 2ϩ release from the endoplasmic reticulum. The selective inhibition of mitochondrial Ca 2ϩ uptake demonstrates that ␣ 2 ␦-1-mediated prolonged Ca 2ϩ signals are buffered by mitochondria, preferentially activated by Ca 2ϩ influx through Ca V 2.2 channels. Thus, by controlling channel abundance at the plasma membrane, the ␣ 2 ␦-1 subunit has a major impact on the organization of depolarization-induced intracellular Ca 2ϩ signaling in dorsal root ganglion neurons.

Proteolytic maturation of α2δ represents a checkpoint for activation and neuronal trafficking of latent calcium channels

“…We therefore examined the effect of α 2 (3C)δ-1 expressed in cultured DRG neurons on native calcium channel currents (Figure 6c). We have previously shown that expression of WT α 2 δ-1 in cultured DRG neurons caused an increase of native calcium currents (D'Arco et al, 2015) (shown with additional data in Figure 6d). Here, we found that expression of α 2 (3C)δ-1 produced a marked reduction in endogenous calcium channel currents in DRG neurons (by 43.2% at +10 mV; Figure 6c,d), supporting the hypothesis that pro-α 2 δ-1 inhibits endogenous DRG calcium currents.…”

Etiology and Pharmacology of Neuropathic Pain

“…This altered activity results from changes in the properties and/or expression of various types of voltage-gated Na + , K + , and Ca 2+ channels (Waxman et al, 1999;Abdulla andSmith, 2001b, 2002;Cummins et al, 2001;Stemkowski and Smith, 2012b;Bourinet et al, 2014;Waxman and Zamponi, 2014;Daou et al, 2016). There are also changes in the function of Na + -K + ATPases (Venteo et al, 2016), intracellular Ca 2+ handling (Hogan et al, 2014;D'Arco et al, 2015;Yilmaz and Gold, 2016;Yilmaz et al, 2017), TRP channels (Basso and Altier, 2017), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Hogan and Poroli, 2008;Emery et al, 2011;Noh et al, 2014;Young et al, 2014).…”

“…In the clinical setting, it is also possible that Ca v 2 channel block may have additional long-term consequences, including effects on gene expression, as has been suggested for Na v 1.7 channels (Deuis et al, 2017;Sexton et al, 2017). Effects of Ca v 2 block may be mediated via long-term changes in intracellular Ca 2+ handling by mitochondria (D'Arco et al, 2015). It is also known that nerve injury downregulates HVA calcium channel current (I Ca ) in DRG neurons (Baccei and Kocsis, 2000;Hogan et al, 2000;Abdulla and Smith, 2001b;Pan et al, 2016).…”

“…Upregulation of a2d subunits increases the expression of Ca v 1 and Ca v 2 a subunits at the plasma membrane as well as calcium current density (Yasuda et al, 2004;Canti et al, 2005;TranVan-Minh and Dolphin, 2010;Dolphin, 2016). The MIDAS motif in the VWA domain of a2d-1 and a2d-2 is responsible for both effects (Canti et al, 2005;Hoppa et al, 2012;D'Arco et al, 2015). In the case of Ca v 1 channels, this involves interaction with extracellular site on the a1 subunit (Walsh et al, 2009).…”

“…In the case of Ca v 1 channels, this involves interaction with extracellular site on the a1 subunit (Walsh et al, 2009). Altered surface expression of Ca 2+ channels has been proposed to exert a secondary effect on mitochondrial Ca 2+ buffering (D'Arco et al, 2015).…”