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.
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