Currents through voltage-gated Ca2+channels (ICa) may be regulated by cytoplasmic Ca2+levels ([Ca2+]c), producing Ca2+-dependent inactivation (CDI) or facilitation (CDF). Since ICa regulates sensory neuron excitability, altered CDI or CDF could contribute to pain generation after peripheral nerve injury. We explored this by manipulating [Ca2+]c while recording ICa in rat sensory neurons. In uninjured neurons, elevating [Ca2+]c with a conditioning prepulse (-15 mV, 2 s) inactivated ICa measured during subsequent test pulses (-15 mV, 5 ms). This inactivation was Ca2+-dependent (CDI), since it was decreased with elimination of Ca2+ influx by depolarization to above the ICa reversal potential, with high intracellular Ca2+ buffering (EGTA 10mM or BAPTA 20mM), and with substitution of Ba2+ for extracellular Ca2+, revealing a residual voltage-dependent inactivation. At longer latencies after conditioning (>6 s), ICa recovered beyond baseline. This facilitation also proved to be Ca2+-dependent (CDF) using the protocols limiting cytoplasmic Ca2+ elevation. Ca2+/calmodulin-dependent protein kinase II (CaMKII) blockers applied by bath (KN-93, myristoyl-AIP) or expressed selectively in the sensoryneurons(AIP)reducedCDF,unlike their inactive analogues. Protein kinaseCinhibition (chelerythrine)hadnoeffect. Selective blockade of N-type Ca2+ channels eliminated CDF, whereas L-type channel blockade had no effect. Following nerve injury, CDI was unaffected, but CDF was eliminated in axotomized neurons. Excitability of sensory neurons in intact ganglia from control animals was diminished after a similar conditioning pulse, but this regulation was eliminated by injury. These findings indicate that ICa in sensory neurons is subject to both CDI and CDF, and that hyperexcitability following injury-induced loss of CDF may result from diminished CaMKII activity.
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