Characterization of voltage gated calcium channels in human sensory neurons

Abstract

Voltage gated calcium channels (VGCCs) in sensory neurons, as with almost all excitable cells, are responsible for initiating a variety of cellular processes ranging from transmitter release to changes in gene expression. VGCCs are also a primary target for a number of drugs in current use to treat pain. Despite their importance, though, there has been no functional characterization of VGCCs in human sensory neurons. To address this knowledge gap, whole cell patch clamp was used to characterize high voltage activating (HVA) voltage-gated Ca2+ current in acutely dissociated human and rat dorsal root ganglion (DRG) neurons. The biophysical properties and relative proportions of pharmacologically-defined HVA current subtypes activated with square or action potential waveforms were assessed, as was the regulation of HVA currents downstream of µ-opioid receptor (MOR) activation. HVA currents in sensory neurons from humans and rats shared general features such as the voltage of activation and suppression following MOR activation. However, we did observe three significant species differences: (1) Ca2+ current density was significantly smaller in human sensory neurons, (2) the proportion of nifedipine-sensitive currents was greater and that of ω-conotoxin IVA-sensitive current was less in human sensory neurons compared to rat, and (3) a subpopulation of human neurons displayed relatively large constitutive inhibition of HVA currents relieved with a depolarizing pre-pulse. While not explored in the rat, there was a significant negative correlation between HVA current density and donor age. These results suggest that there may be far more extensive compartmentalization of intracellular signaling processes in human sensory neurons, and that it may be necessary to re-evaluate the current subtypes targeted for therapeutic interventions to treat pain. R01DK107966,R01AR063772, UG3TR003090.