The Upregulation of {alpha}2{delta}-1 Subunit Modulates Activity-Dependent Ca2+ Signals in Sensory Neurons

As auxiliary subunits of voltage-gated Ca²⁺ channels, the α₂ proteins modulate membrane trafficking of the channels and their localization to specific presynaptic sites. Following nerve injury, upregulation of the α₂-1 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 α₂-1 in rat sensory neurons leads to prolonged Ca²⁺ responses evoked by membrane depolarization. This mechanism is coupled to Ca_V2.2 channel-mediated responses, as it is blocked by a -conotoxin GVIA application. Once initiated, the prolonged Ca²⁺ transients are not dependent on extracellular Ca²⁺ and do not require Ca²⁺ release from the endoplasmic reticulum. The selective inhibition of mitochondrial Ca²⁺ uptake demonstrates that α₂-1-mediated prolonged Ca²⁺ signals are buffered by mitochondria, preferentially activated by Ca²⁺ influx through Ca_V2.2 channels. Thus, by controlling channel abundance at the plasma membrane, the α₂-1 subunit has a major impact on the organization of depolarization-induced intracellular Ca²⁺ signaling in dorsal root ganglion neurons.